Opioid and anti-opioid peptides

Fundam Clin Pharrnacol(1995) 9 , 4 0 9 4 3 3 Q Elsevier, Paris

409

Review

Opioid and anti-opioid peptides

F Cesselin

Inserm U 288 and Service de Biochimie Mkdicale, Faculte‘ de Mkdecine, Pitik-Salpt?trit?re, 91 Boulevard de 1’Hbpital. 75634 Paris cedex 13, France

(Received 12 April 1995; accepted 9 June 1995)

Summary - The numerous endogenous opioid peptides (pendorphin, enkephalins, dynorphins ...) and the exogenous opioids (such as morphine) exert their effects through the activation of receptors belonging to four main types: p, 6, rand E. Opioidergic neurones and opioid receptors are largely distributed centrally and peripherally. It is thus not surprising that opioids have numerous pharmacological effects and that endogenous opioids are thought to be involved in the physiological control of various functions, among which nociception is particularly emphasized. Some opioid targets may be components of homeostatic systems tending to reduce the effects of opioids. “Anti-opioid” properties have been attributed to various peptides, especially cholecystokinin (CCK). neuropeptide FF (NPFF) and melanocyte inhibiting factor (MIF)-related peptides. In addition, a particular place should be attributed. paradoxically, to opioid peptides themselves among the anti-opioid peptides. These peptides can oppose some of the acute effects of opioids. and a hyperactivation of anti-opioid peptidergic neurones due to the chronic administration of opioids may be involved in the development of opioid tolerance andor dependence. In fact, CCK, NPFF and the MIF family of peptides have complex properties and can act as opioid-like as well as anti-opioid peptides. Thus, “opioid modulating peptides” would be a better term to designate these peptides, which probably participate, together with the opioid systems, in multiple feed-back loops for the maintenance of homeostasis. “Opioid modulating peptides” have generally been shown to act through the activation of their own receptors. For example, CCK appears to exert its anti-opioid actions mainly through the activation of CCK-B receptors, whereas its opioid-like effects seem to result from the stimulation of CCK-A receptors. However, the partial agonistic properties at opioid receptors of some MIF-related peptides very likely contribute to their ability to modulate the effects of opioids. CCK- and NPFF-related drugs have potential therapeutic interest as adjuncts to opioids for alleviating pain andor for the treatment of opioid abuse.

opioid peptides I morphine 1 anti-opioid peptides 1 cholecystokinin 1 neuropeptide FF I MIF I analgesia 1 opioid tolerance I opioid dependence

INTRODUCTION

In addition to pain inhibitory pathways, which include endogenous opioid systems, several lines of evidence suggest that there are “anti-analgesic’’ neuronal peptide systems which act in an opposite manner by blocking pain inhibition. As these systems can oppose not only the analgesic actions of opioids but also certain others of their pharmacological or physiological effects, they can be more generally referred as to “anti-opioid” systems. Besides reducing the acute effects of opioids, the triggering of these systems by opioids themselves could explain, at least partly, the development of tolerance and dependance to opioids. Currently available data, which will be summarized below, show that the three most studied “anti-opioid” peptides (cholecystokinin [CCK], neuropeptide FF

[NPFF] and peptides of the melanocyte-inhibiting factor [MIF] family) in fact have complex properties: they can act as anti-opioid as well as opioid- like peptides. This suggests that “opioid modulating peptides” would be a better term to designate these peptides, and that the systems of multiple feed-back loops they actually form with the opioid systems take place within the framework of the classical and general concept of homeostasis.

THE OPIOID PEPTIDES AND THEIR RECEPTORS

Introduction

To date, numerous endogenous opioid peptides (“endomorphins”) have been identified which are synthesized by neurones widely distributed in both

410 F Cesselin

ACTH 5LPH

PC1 PROOPlOMEUNOCORTlN (POMC)

I COOH

I PC1, Pc2 a-MSH

0 i B-ENDORPHIN

11-13,

I metenkephalin sequence : Tyr-Gly-Gly-Phe-Met 1 0 2 7

8-ENDORPHIN-1-26 n26 Fig 1. Schematic representation of proopiomelanocortin and its main derivatives. In addition to the peptides represented in this figure, others also generated from POMC have been identified. In the anterior lobe of the pituitary, POMC is mainly cleaved to produce ACTH and PLPH by the proprotein convertase PC1. Due to the presence of proprotein convertase PC2, together with PCI, the main products of POMC in the intermediate lobe of the pituitary and the CNS are Pendorphin and a-MSH. Pendorphin (in its initial form, 1-31) and its shorter forms (1-27 and 1-26) lose their opioid activity when they are acetylated (not shown). Pendorphin-1-31 and P endorphin- 1-27 act as agonist and antagonist, respectively, at opioid receptors.

the central and the peripheral nervous systems. These peptides act at specific receptors, which belong to several types also largely distributed centrally and peripherally. It is thus not surprising that opioids have numerous pharmacological effects and that endogenous opioids are thought to be involved in the physiological control of various functions, among which nociception is particularly emphasized (see Millan, 1986).

At least twenty peptides form the group of endomorphins. All of them have in common the amino acid sequence of their N-terminal moiety: Tyr- Gly-Gly-Phe-Met, or Tyr-Gly-Gly-Phe-Leu. These pentapeptide sequences are by themselves the two shortest endomorphins, ie met-enkephalin and leu- enkephalin, respectively. The endogenous opioid peptides originate from three distinct precursors: proopiomelanocortin (POMC), proenkephalin A (PA), and prodynorphin (PD), also called proenkephalin B.

The proopiomelanocortin (POMC) family of peptides (fig 1)

The POMC gene is mainly expressed in the anterior pituitary and the central nervous system

(CNS). It can also be expressed in immune cells of inflamed tissue (Przewlocki et al, 1992). As indicated by its name, POMC is the precursor of opioid, melanotropic (MSH) and corticotropic (ACTH) peptides. Depending on the proprotein convertases (PC1, PC2 ...) which act upon it, POMC is cleaved mainly to form ACTH and p lipotropin (P-LPH) (in the anterior lobe of the pituitary), or in Pendorphin (a 31 amino acid peptide acting as an agonist at opioid receptors) and a-MSH (in the intermediate lobe and the CNS) (see Loh, 1992). pendorphin-1-31 can be further cleaved into pendorphin- 1-27 (&endorphin) and pendorphin-1-26 (fig 1). Endorphins can be acetylated, a modification which leads to the loss of their opioid activity (see Loh, 1992). Such trans- formations probably have important physiological significance. For instance, pendorphin- 1-27 (in its non acetylated form) blocks the analgesic effect of pendorphin-1-3 1 with a potency five-fold higher than that of the most commonly used opioid antagonist, naloxone (Hammonds et al, 1984). In other words, the same precursor, POMC, can generate peptides with opposite biological activities.

POMC is synthesized by neurones located in the hypothalamus (essentially in the arcuate nucleus)

Opioid and anti-opioid peptides 41 1

I I I 0 7

O I I 0 Proenkephalln A

II I I I COOH , Synenkephaiin , , PeptideF , Amidorphln

0 I metenkephalin sequence (TyrGly-Gly-Phe-Met)

leu-enkephalln sequence (Tyr-Gly-Gly-Phe-Leu) P

Adrenomhln

8 0 octapeptide

7 - heptapeptide

Fig 2. Schematic representation of proenkephalin A and its main derivatives. When all potential sites are cleaved (a frequent situation in the CNS), each precursor molecule yields 7 endomorphin molecules:4 of met-enkephalin, one of leu-enkephalin, one of an octapeptide (8) and one of a heptapeptide (7). However, proenkephalin A can be processed differently to generate longer peptides (peptide E, adrenorphin etc).

and in the brain stem (principally the nucleus tractus solitarius). Hypothalamic POMC neurones have very diffuse projections in the brain, notably in hypothalamic and limbic areas. Several struc- tures (such as the thalamus, the periaqueductal gray [PAG] and the reticular formation) involved in nociception contain POMC terminals.

The proenkephalin A (PA) family of peptides (fig 2)

PA is mainly synthesized in the adrenal medulla (of some species) and the CNS. Like POMC, PA can also be expressed in immune cells (Przewlocki et al, 1992). Each molecule of PA contains seven sequences of endomorphins. There is also a vari- ability in the processing of PA, and a large number of different opioid peptides can derive from h s precursor. In the CNS, the major ones are met- and leu-enkephalins, a heptapeptide: met-enkephalin- Arg6-Phe7, an octapeptide: met-enkephalin-Arg6- Gly7-Leu8, and a C-terminal-amidified 8 amino acid peptide (adrenorphin or metorphamide), the latter being present in substantial amounts mainly in the hypothalamus, striaturn and spinal cord (fig 2).

PA synthesizing neurones are numerous and largely distributed. They are found mainly in the striatum, cerebral cortex, olfactory tubercle, hippocampus, septum, several hypothalamic and thalamic nuclei, PAG and the dorsal horn of the spinal cord. They are mainly interneurones, although some of them send long projections such as, for instance, those which form an enkephalinergic pathway between the posterior raphe nuclei and the dorsal horn of the spinal cord (see Khachatu- rian et al, 1985). Enkephalins are also present in peripheral neurones, notably in some primary afferent fibres which convey sensory information from the periphery to the dorsal horn (Pohl et al, 1994).

The prodynorphin (PD) family of peptides (fig 3)

The gene encoding of the third precursor of endomorphins, PD, is mainly expressed in the CNS, the adrenals and the anterior pituitary. Each molecule of PD contains three leu-enkephalin sequences. Indeed, in some areas, like the substantia nigra, leu-enkephalin can actually arise from PD. How- ever, the main products of PD are in fact longer

412 F Cesselin

Prodynorphin (Proenkephalin B)

Dynorphln 1-32 a-Neo-endorphin

leuenkephalin sequence (Tyr-GlyGly-Phe-Leu) I Dynorphin B P-Nwndorphin 1-17 1-29

Fig 3. Schematic representation of prodynorphin (or proenkephalin B) and its main derivatives. Each prodynorphin molecule is poten- tially processed into 3 opioid peptide molecules. Processing enzymes can generate leu-enkephalin, but the main derivatives of prodynorphin are peptides of higher molecular weight (neo-endorphins. dynorphins A and B).

peptides, ie neoendorphins and dynorphins A and B (fig 3). In the CNS, the distribution of neurones synthesizing PD is as large as (and apparently very close to) that of PA neurones (see Khachaturian el al, 1985). The two peptide families even coexist in some neurones of the raphe nuclei and the dorsal horn of the spinal cord. However, in a given structure, the distributions of PA and PD neurones are most often distinct. As enkephalins, PD derived peptides, especially dynorphins, are expressed in at least some sensory neurones (Basbaum et al, 1986; Sweetnam et al, 1986; Weihe et al, 1985).

The opioid receptors

Endomorphins and exogenous opioids exert their physiological and pharmacological effects, respectively, by interacting with opioid receptors belonging to four main types, which can be divided into subtypes: y Wll 4). a (a,, a,), K(K,, %, K3) and E. In addition, opioid receptors can be associated in complexes with mixed p, a andor ~properties, in which 'allosteric interactions can occur, such that the binding of a given opioid agonist (a selective for instance) can non-competitively affect the binding of another ligand (p selective for example) (see Holaday et al, 1991).

Although they were discovered more than 20 years ago, representatives of the first three types, with pharmacological properties close to those of the y,, a2 and K, receptors, respectively, have only recently been cloned (see Chen et al,

1993; Reisine and Bell, 1993; Uhl ef al, 1994). By contrast, E opioid receptors remain poorly known. Cloning of opioid receptors has confirmed that they belong to the superfamily of G protein-coupled receptors. Their effectors can be enzymes (like adenylate cyclase) or ion channels (K+, Ca2+).

The various opioid receptors can be distin- guished from each other owing to agonist and antagonist ligands, discovered andor synthesized during the last years, which exhibit a much higher affinity for a given type of receptor than for the others. When they are used at concentrations or doses such that their binding to the receptors with which they interact with a low affinity remains negligible, they act as selective ligands of a given opioid receptor type. However, except in a few cases, endogenous ligands, endomorphins, have a relatively weak selectivity for the various opioid receptors types. Opioid receptors are widely distributed in the CNS and the peripheral nervous system (see Collin and Cesselin, 1993 and refs therein).

Possible functions of opioid systems

The wide distributions of the opioidergic neurones and opioid receptors suggest that the endomorphinergic systems play various physiological roles. Indeed, evidence has been presented for their implication in the control of respiratory, cardiovascular and gastrointestinal functions, pituitary hor-

Opioid and anti-opioid peptides 413

monal secretion, motor activity, and the etiology of some pathological states such as epilepsy and psychosis (see Olson et al, 1994).

One of the better established functional roles of the opioid systems is the control of nociception. Thus, morphine, or more generally opioids, could exert their analgesic effects by mimicking a physiological mechanism normally involving endomorphins (see Millan, 1986). The neuroanatomi- cal substrate for this action exists, since the spinal and cerebral areas involved in nociception (dorsal horn of the spinal cord, PAG, some thalamic nuclei etc) all contain endomorphinergic neurones and opioid receptors. Opioid receptors are also present on the peripheral terminals of the primary afferent fibres which convey nociceptive mes- sages. These receptors could be activated by opioid peptides locally released from immunocytes (see above). Thus, although the details of their involvement in physiological or pathological situations are far from being clearly elucidated, it is very likely that endogenous (and exogenous) opioids decrease the transmission of nociceptive mes- sages by acting at numerous strategical points on the pain pathways, from the periphery to the cerebral cortex, including the spinal, bulbo-mesence- phalic and thalamic relays etc (see Cesselin, 1991 and refs therein).

ANTI-OPIOID PEPTIDES

Introduction

Endogenous and exogenous opioids affect the activity of the neurones which express opioid receptors, and numerous neuronal networks, involving various neurotransmitters, are implicated in the diverse physiological or pharmacological effects of opioids. Some opioid targets may participate in a homeostatic system tending to reduce the effects of opioids. Thus, opioids could activate neurones that would release neuropeptides with “anti-opioid” properties. Such peptides would be able to reduce some of the acute (particularly antinociceptive) effects of endogenous or exogenous opioids, while the blockade of their receptors would enhance the effects of opioids. According to this concept, the effects of opioids should be per- manently lowered due to the triggering of anti-opioid systems (fig 4).

It is well known that chronic administration of opioids can lead to the development of tolerance to some of their pharmacological effects, as well as to a state of dependence. Blocking the action of some anti-opioid peptides can reduce tolerance and

+ - EFFECTS

Fig 4. General concept of anti-opioid peptides. In this figure, as in the following ones, the term “effects” is used for desig- nating both pharmacological and physiological effects, whatever the level at which they are appreciated (from the molecular to the behavioural level). However, most of the data obtained relate to nociception and analgesia. Opioids, either exogenous or endogenous, activate neurones which release neuropeptides acting as endogenous “antagonists” of opioids, by reducing their pharmacological or physiological effects. These “anti-opioids” can exert an excitatory influence on opioidergic neurones, leading to an enhancement of the release of endogenous opioid peptides.

attenuate the withdrawal syndrome. These observations have led to the idea that hyperactivation of anti-opioid peptidergic neurones due to the chronic administration of opioids may be responsible, at least partly, for the development of opioid tolerance andor dependence.

“Anti-opioid” properties have been attributed to various peptides including TRH (Bhargava et al, 1983; Holaday et al, 1978; Tache et al, 1977), somatostatin (Terenius, 1976), calcitonin (Giusti et al, 1985), ACTH (Bertolini et al, 1979; Galina and Amit, 1985; Smock and Fields, 1981; Terenius, 1976; Terenius et al, 1975), a-MSH (Contreras and Takemori, 1984a, b; Sandman and Kastin, 1981), and arginine vasopressin (Xu et al, 1992), but the most studied anti-opioid peptides have been cholecystokinin (CCK), neuropeptide FF (NPFF) and melanocyte inhibiting factor (MIF) and its derivatives (table I). Excellent reviews have already been devoted to these peptides (see Baber et al, 1989; Galina and Kastin, 1986; Reed et al, 1994; Rothman 1992) and the purpose of the present review is to take stock of the present knowledge of the possible implication of these three peptides in opioid tolerance andor dependence.

In addition to CCK, NPFF and MIFs, a particular place should be attributed, paradoxically, to opioid peptides themselves among the anti-opioid peptides. We will begin with some brief considera- tions on this issue before summarizing in greater detail the anti-opioid properties of CCK, NPFF and MIFs.

414 F Cesselin

Table I. Amino acid sequences of cholecystokinin-8 (CCK), neuropeptide FF (NPFF) and rnelanocyte inhibiting factor (M1F)-related peptides.

Cholecystokinin-8 (CCK): Asp-Tyr-Met-Gly-Trp-Met-Asp-Phe-NH, Neuropeptide FF (NPFF): Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-Nh, Melanocyte inhibiting factor (MIF)-related peptides: Pro-Leu-Gly-NH, (MIF- 1 )

Tyr-Pro-Leu-Gly-NH, (Tyr-MIF- 1 ) Tyr-Pro-Trp-Gly-NH, (Tyr-W-MIF- 1 ) Tyr-Pro-Lys-Gly-NH, (Tyr-K-MIF- 1)

Opioid peptides as anti-opioids

Some opioids can reduce or block the effects of other opioids. Thus, as noted above, one of the derivatives of POMC, P-endorphin- 1-27, can inhibit the antinociceptive activity of pendorphin- 1-31 (Hammonds et al, 1984; Suh et al, 1988; Takemori and Portoghese, 1993). When both compounds are administered intracerebroventricularly (icv) to mice, the antagonistic activity of pendorphin-1-27 appears to be mediated through 3, opioid receptors (Takemori and Portoghese, 1993). Alterations in the processing of POMC leading to an enhanced production of this antagonist have been proposed to be responsible, in part, for the development of tolerance to the analgesic effect of opioids after chronic administration of morphine (Bronstein et al, 1990).

In line with the possible existence of opioid receptor complexes (see above), or of interactions between various neuronal systems beyond the receptors, dynorphins and synthetic opioid agonists acting at K receptors have been shown to modulate the effects due to the stimulation of p or 3 receptors. In particular, endogenous and exogenous K agonists have been shown to block the effects of morphine and other opioid agonists on various parameters on which they are devoid of effects by themselves (Dickenson and Knox, 1987; Friedman et al, 1981; Fujimoto and Arts, 1990; Fujimoto and Holmes, 1990; Fujimoto et al, 1990; Hong et al, 1988; Janiri et al, 1988; Katoh et al, 1990; Lee and Smith, 1984; Miaskowski et al, 1992; Petrillo et al, 1984; Ramabadran, 1983; Ramarao et al, 1988; Schmauss and Herz, 1987; Sheldon et al, 1987, 1988, 1989; Tulunay et at, 1981; Wood et al, 1983). For instance, although icv administered dynorphin exerts no effect on its own, it significantly reduces morphine- and P- endorphin- 1-3 l-induced antinociception (Fried- man et al, 1981; Tulunay et al, 1981). In addition, electrophysiological studies revealed that the inhibition of spinal neurones by p agonists is less pronounced upon IC opioid receptor stimulation (Dick- enson and Knox, 1987). In our laboratory, we

demonstrated that the stimulation of K receptors, without any effect by itself, can modulate the influence of p receptor stimulation on the release of met-enkephalin-, CCK-, substance P- and CGRP-like materials from the rat spinal cord, in vivo as well as in vitro (Benoliel et al, 1991, 1994; Collin et al, 1992a, b, 1993, 1994).

Although the stimulation of opioid receptors (including those which have been cloned) is classi- cally known to trigger inhibitory effects (decrease in intracellular CAMP levels, hyperpolarization, reduction in the release of neurotransmitters etc), through the activation of pertussis toxin-sensitive G proteins (ie Gi/Go), increasing evidence supports the existence of opioid receptors, with a high affinity for agonists, which are coupled to cholera toxin-sensitive G proteins (ie Gs) and whose stimulation leads to excitatory effects (see Crain and Shen, 1990; Gintzler and Xu, 1991; Lin and Car- penter, 1994; Wang and Gintzler, 1994). Further- more, opioid receptors in a given cellular type can interact simultaneously with both GdGo and Gs proteins (Cruciani et al, 1993). In other words, the net effects of opioids will depend on their relative excitatory influence through the activation of receptors (with high affinity for the agonists) coupled to Gs proteins and inhibitory influence mediated by receptors (with a lower affinity) coupled to GdGo proteins. Thus, Crain and Shen have shown that chronic administration of an opioid agonist leads to a reduction in its inhibitory influence together with an increase in its excitatory action (Crain and Shen, 1992; Shen and Crain, 1992). Such alterations have been proposed to be implicated in the development of the tolerance to the inhibitory effects of opioids and in the opioid withdrawal syndrome (Shen and Crain, 1994).

Cholecystokinin

Introduction Cholecystokinin was first identified as a hormone in the gastrointestinal system. It was subsequently shown to be present in the CNS (Vanderhaeghen e f al, 1975), essentially in its sulfated octapeptide


Table 11. Main antagonists of CCK receptors.

Nonselective Proglumide

CCK-A Devazepide (MK-329, L-364,7 18) Benzotript

Lorglumide (CR-1409) L-365,03 1

CCK-B L-365,260 Cl-988 (PD-134,308) PD-135,158

form (CCK, Rehfeld, 1985; table I). At least two types of CCK receptors (A and B) have been identified (Moran et al , 1986). Although CCK-A “alimentary” receptors are found primarily in the periphery, they are also present in some brain areas. CCK-B “brain” receptors have a widespread distribution in the CNS. Selective agonists and antagonists at these two types of CCK receptors, which have been recently cloned, are available (see refs in Crawley and Corwin, 1994) (table 11).

There is a striking overlap in the anatomical distributions of CCK, opioid peptides and their respective receptors in the CNS (Stengaard-Peder- sen and Larsson, 1981; Zabin et al, 1983). Both CCK and opioids are localized within principal nociceptive centres, including layers I and I1 of the spinal cord, the PAG, and intralaminar nuclei of the thalamus. They coexist in some neurones of the thalamus, PAG, and allocortex (Gall et al, 1987).

CCK and opioids have been shown to exert opposite effects in several experimental paradigms and physiological functions. For instance, in rats, food intake increases following administration of opioid agonists, but decreases following administration of CCK (see Baile e t al, 1986, for a review). At the cellular level, CCK and opioids are also known to act frequently in an opposite way, as shown for instance on ion transport in the intestine (Kachur et al, 1980, 1991). Indeed, as summarized below, CCK frequently acts as an anti-opioid compound, especially in pain processing and control.

CCK as an anti-opioid peptide The results of numerous studies support this asser- tion. Thus, it has been shown that CCK antagonizes butorphanol-induced feeding (Morley et al, 1983), morphine’s effects on locomotor activity (Schnur et al, 1986), and pendorphin-induced catalepsy (Itoh and Katsuura, 1981) and disruption of maternal behaviour (Felicio et al, 1991). Similarly, CCK reduces the hypothermic (Kapas et al, 1989) and hypotensive effects of opioids (Mei and Han,

1993), as well as the excitation of pyramidal neurones due to opioid receptor activation in the rat hippocampus (Miller and Lupica, 1994). In addition, CCK blocks the increase in brain tryptophan hydroxylase activity elicited by morphine (Johannessen et al, 1989) and prevents &endorphin from inhibiting brain and liver DNA synthesis in rat pups (Bartolome et af, 1994). However, as summarized below, the majority of experiments have been devoted to the anti-analgesic effects of CCK.

CCK as an anti-analgesic peptide

Effects of exogenous CCK

CCK reduces the antinociceptive effects of exogenous opioids Numerous reports have indicated that CCK antagonizes opioid antinociceptive effects. Indeed, administered by peripheral or central (icv, intrathecal) routes, CCK can reduce morphine-, PL017- or ohmefentanyl- (two selective p agonists), and p endorphin-induced analgesia, as well as the morphine-induced depression of the nociceptive flex- ion reflex in rats (Faris et al, 1983; Han et al, 1985; Itoh et al, 1982; Li and Han, 1989; Suh et al, 1992; Wang et al, 1990; Wiesenfeld-Hallin and Duranti, 1987; Wiesenfeld-Hallin and Xu, 1993; Zhang et at, 1994). In the mouse tail flick test, CCK attenuates the analgesic effects of morphine (Barbaz et al, 1989). In addition, in the same species, CCK administered intrathecally antagonizes the inhibition of tail-flick by icv j3-endorphin (Tseng and Collins, 1992). Furthermore, the inhibitory effect of morphine and DAGO on C fibre- evoked activity of rat spinal nociceptive neurones can be reduced by CCK (Kellstein et al, 1991; Magnuson et al, 1990; Suberg et al, 1985a, b).

Thus, from these data, it can be concluded that CCK has the pharmacological property of reducing the antinociceptive effects of exogenous opioids.

CCK reduces the antinociceptive effects of endogenous opioids Several observations suggest that exogenous CCK can also reduce the analgesia due to endogenous opioids. Indeed, CCK blocks the naloxone-sensitive analgesia in rats subjected to forepaw shocks or in rats conditioned to these shocks (Faris, et al, 1983). In addition, in the same species, CCK attenuates opioid analgesia induced by restraint stress (Dourish et al, 1988a). Finally, CCK antagonizes electroacupuncture-induced analgesia, which is thought to be mediated through the release of endomorphins

41 6 F Cesselin

(Chen et al, 1994; Han and Terenius, 1982; Han et al, 1986), as well as the acupuncture-induced suppression of the electrical activity of thalamic pain- related neurones in the rat (Bian et al, 1993).

Studies with CCK receptor antagonists as tools for establishing the role of endogenous CCK CCK antagonists potentiate the antinociceptive effects of exogenous opioids A large amount of data strongly suggests that the above summarized effects of exogenous CCK in fact mimic the action of the endogenous peptide. Thus, active immunization against cholecystokinin or administration of an anti-CCK antiserum potentiate morphine and Pendorphin analgesia in rats (Faris et al, 1984; Itoh et al, 1985; see also Ding et al, 1986).

Proglumide, a non-selective CCK receptor antagonist, and the selective CCK-A antagonists, devazepide and lorglumide, enhance opioid analgesia in rodents and baboons (Bodnar et al, 1990; Dourish et al, 1988b, 1990b; Hendrie et af, 1989; Katsuura and Itoh, 1985; Kellstein and Mayer, 1990; Kellstein et al, 1991; Klein et al, 1992, Lavigne et al, 1992; Li and Han, 1989; O'Neill et al, 1989; Panerai et al, 1987; Poggioli et al, 1991; Rattray et al, 1988; Rovati et al, 1985; Suh and Tseng, 1990; Takeshige et al, 1991; Tang et al, 1984a; Watkins et al, 1984, 1985a, b, c; Zhou et al, 1993b). Proglumide also potentiates the inhibitory effect of intrathecal morphine on the electrical activity of spinal nociceptive neurones (Suberg et al, 1985b).

In addition to enhancing opioid antinociception in rodents and squirrel monkeys, the CCK-B antagonist, L-365,260, produces by itself an analgesic effect in the latter species (Dourish et al, 1990a; Lavigne et al , 1992; Maldonado et al, 1993; O'Neill et al, 1990; Ossipov et al, 1994; Zhou et ul , 1993b). In the rat, another CCK-B antagonist, CI-988, also enhances the analgesic effect of morphine on the flexor reflex, and exerts a naloxone-reversible antinociceptive effect per se (Wiesenfield-Hallin and Xu, 1993; Wiesenfield- Hallin e t al , 1990, 1991). Moreover, it was recently shown that treatment with antisense oligo- nucleotides targeting the cloned CCK-B receptor produces a 5-fold leftward displacement of the morphine analgesic dose-effect curve (Vanderah et al, 1994).

Interestingly, an induction of the expression of the proCCK gene has been observed in rat dorsal root ganglia after peripheral axotomy, a model of neuropathic pain, which induces autotomy behaviour (Xu et al, 1993). Furthermore, this behaviour

can be inhibited by combined treatment with morphine and the CCK-B antagonist CI-988 (Xu et al, 1993). In axotomized rats, the depressive effect of CI-988 on the flexor reflex is more pronounced than in normal animals, and the (weak) inhibitory influence of morphine on this reflex is enhanced by CCK-B receptor blockade by this antagonist (Xu et al, 1994b). These observations led the authors to propose that an increased release of CCK from terminals of (lesioned) primary afferent fibres could antagonize the actions of opioid analgesics either released endogenously or applied exogenously, resulting in the development of a neuropathic pain syndrome and in the ineffective- ness of opioids. Similarly, in another model of neuropathic pain due to photochemically provoked spinal cord ischemia, CI-988 (but not CAM 1481, a selective CCK-A antagonist) relieves the lesion- induced allodynia-like symptoms (Xu et al , 1994a).

The importance of the pain state to reveal the possible anti-analgesic action of endogenous CCK is further demonstrated by the observations of Stanfa and Dickenson (1993). These authors showed that CCK-B receptor blockade by L- 365,260 or PD 135158 potentiates the inhibitory effect of intrathecal morphine or DAGO on the C- fibre-evoked responses of dorsal horn nociceptive neurones in normal rats (Stanfa and Dickenson, 1993; Sullivan et al, 1994) but not in animals with carrageenin-induced inflammation (Stanfa and Dickenson, 1993). Conversely, CCK attenuates the effects of morphine only in rats with carrageenin inflammation (Stanfa and Dickenson, 1993). The effects of both CCK and its antagonists L- 365,260 and PD 135138 are therefore dependent on the inflammatory state of the animal, with the agonist and the antagonists being active in opposite situations. This led to the proposal that in normal rats morphine may produce a maximal stimulation of CCK release, such that exogenous CCK is unable to further reduce the opioid analgesia, whereas in rats with inflammation there is a reduction in the spinal release of CCK, which could explain the enhanced potency of morphine in these animals (Stanfa and Dickenson, 1993; Stanfa et al, 1994).

More generally, the experimental context seems to be critical with regard to the anti-analgesic action of CCK. In line with this view, Lavigne et al. (1992) showed that the CCK-A and CCK-B receptor antagonists, devazepide and L-365,260, enhance morphine antinociception only in non-acclimated rats exposed to a novel environment.


CCK antagonists enhance the antinociceptive effects of endogenous opioids In agreement with the idea that electroacupuncture not only triggers the release of endogenous opioids (Han and Terenius, 1982), but also that of CCK, which may limit the analgesic effects of endomorphins, CCK-B receptor blockade by L-365,260 (intrathecal injection) has been shown to enhance electroacupuncture analgesia in the rat (Zhou et al, 1993a). Similarly, restraint stress-induced analgesia can be increased by CCK antagonists (Dourish et al, 1988a). Furthermore, the antinociceptive responses induced by endogenous enkephalins (fully protected from their catabolism by a com- plete inhibitor of the enkephalin-catabolizing enzymes) are strongly potentiated by the CCK-B receptor antagonists L-365,260, CI-988 and RB 21 1 in both rats and mice (Maldonado et al, 1993; Valverde et al, 1994).

Whereas neural circuitry that produces analgesia can be activated by a variety of environmental events (conditioned analgesia), this is also true for anti-analgesia systems: safety signals could become inhibitors of analgesia, either conditioned (and due to the triggering of endogenous opioid systems) or induced by morphine (Wiertelak et al, 1992). CCK appears to be involved in the media- tion of conditioned anti-analgesia at the spinal cord level. Indeed, proglumide abolishes the ability of a safety signal to block intrathecal morphine analgesia (Wiertelak et al, 1994).

Conclusion (fig 5 )

That the consequences of proglumide administration may in fact be due to its direct interaction with opioid receptors has been suggested due to its agonistic properties at ? opioid sites (Rezvani et al, 1987). Similarly, benzotript and lorglumide have high affinity for both CCK and opioid receptors (Gaudreau et al, 1990). Such properties do not apply to the other CCK antagonists, including devazepide, L-365,260 and CI-988, which do not bind to opioid receptors (Gaudreau et al, 1990; Hughes et al, 1990). Thus, altogether, these data indicate that endogenous CCK tends to reduce the antinociceptive action of exogenous as well as endogenous opioids by acting primarily at CCK receptors.

It would seem that the anti-opioid effects of CCK arise as a result of the stimulation by the peptide of CCK-B rather than CCK-A receptors. Indeed, the rank order of potency of the CCK antagonists (L-365,03 1, devazepide and L- 365,260) in potentiating morphine analgesia in the

DELTA

OPlOlDS CCK

EFFECTS Fig 5. Schematic representation of CCWopioid interactions. Opioids, either exogenous or endogenous, could activate (through 6 opioid receptors) CCKergic systems, and CCK, through CCK-B receptors, could reduce the opioid effects. In turn, CCK, or exogenous agonists, through an action at CCK-A receptors, could increase the release of endogenous opioid peptides, and facilitate opioid-mediated effects.

rat correlates with their affinity for CCK-B receptors (Dourish et al , 1990a). For instance, L- 365,260 appears to be 5 to 20 times more potent than devazepide both in potentiating morphine analgesia in rodents and in blocking CCK-B receptor activation (Dourish et a1, 1990a). Moreover, in contrast to selective CCK-B antagonists, neither lorglumide nor devazepide, two CCK-A antagonists, are able to potentiate antinociception mediated by endogenous enkephalins (Maldonado et al, 1993).

The data summarized above suggest that exogenous and endogenous opioids very likely activate CCKergic systems, leading to increased extracellular levels of CCK which counteract the antinociceptive actions of opioids. Surprisingly, the ability of opioids to actually enhance the release of CCK has been investigated in relatively few studies. However, it was shown, in both in vivo and in vitro experiments, that, although p opioid agonists reduce the release of CCK, morphine and 6 opioid agonists increase the outflow of this peptide from various central areas (Benoliel et al, 1991, 1992, 1994; Rattray and de Belleroche, 1987; Rodriguez and Sacristan, 1989; Tang et al, 1984a; Zhou et al, 1993b). Furthermore, in rat brain, the in vivo binding of a selective tritiated CCK-B agonist (BC 264) is reduced by a selective 6 agonist or by pro- tecting enkephalins from degradation, strongly suggesting that endogenous enkephalins increase

418 F Cesselin

the extracellular levels of CCK through activation of 6 receptors (Ruiz-Gay0 et al, 1992).

Involvement of CCKergic systems in the development of opioid tolerance Chronic use of various types of drugs, including opioids, results in adaptive changes that lead to the development of a loss of responsiveness to the drug used (tolerance) andor of a state in which the drug is required for the maintenance of normal physiological functions (dependence). Neurobio- logical mechanisms of opioid tolerance and dependence are still poorly understood. Various changes (down- and/or up-regulation) affecting opioid receptors and the postreceptor mechanisms (functional uncoupling from G protein) have been suggested to be responsible for these phenomena (see Collin and Cesselin, 199 1, for a review). However, cessation of stimulation of opioid receptors, by disruption of opioid administration or administration of an opioid antagonist, leads to a withdrawal syndrome with various behavioural manifestations. Moreover, as an animal becomes more tolerant to morphine, less naloxone is required to trigger the withdrawal syndrome (see Rothman, 1992 for review and discussion). This suggests that during a chronic opioid treatment, opioid receptors remain stimulated, stimulatable, and can be blocked, properties which are not easily reconcilable with the tolerance mechanisms proposed above, particularly those implicating a desensitization (whatever its cause) of opioid receptors. Without excluding the role of adaptive changes at the level of the receptors, the hypothesis of an opioid-induced compensatory hyperactivity of anti-opioid systems could offer an additional explanation for the development of opioid tolerance and dependence.

A large amount of data supports the idea that CCKergic systems might play a major role in the development of opioid tolerance. Thus, in conditions where chronic morphine administration results in the development of tolerance to its analgesic effects, daily administration of proglumide or of selective CCK-A or CCK-B receptor antagonists, during the whole period of morphine treatment, inhibits the development of tolerance to the drug (Dourish et al, 1988b, 1990a; Kellstein and Mayer, 1991; Panerai et al, 1987; Rovati et al, 1985; Watkins et at, 1984; Wiesenfeld Hallin and Xu, 1993; Xu et al, 1992). Similarly, the acute desensitization to morphine (induced in 14 hours by repeated morphine injections) can be reduced by proglumide (Tang et al, 1984a). Furthermore, although active immunization against CCK does not affect morphine tolerance (Faris et al, 1984),

icv or intrathecal injection of an anti-CCK antiserum reverses tolerance to morphine in rats (Ding et al, 1986). Not surprisingly, since the same anti- opioid activity of CCK as that implicated in its anti-analgesic effects is assumed to be. involved, the CCK receptors more likely implicated in the prevention of morphine tolerance appear to be those of the B type (Dourish et al, 1990a; Wood- ruff and Hughes, 1991; Xu et al, 1992). Moreover, it was recently shown that the CCK-B receptor antagonist CI 988 is not only able to block the development of morphine tolerance but also able to reverse tolerance to the analgesic effects of morphine in the hot plate test: in rats rendered tolerant, a significant degree of antinociception is observed when CI 988 is administered together with morphine (Hoffmann and Wiesenfeld-Hallin, 1994).

Interestingly, the naloxone-precipitated withdrawal syndrome is not affected by daily CCK antagonist administration (Dourish et al, 1988b, 1990a; Panerai et al, 1987; Rovati et at, 1985; Xu et al, 1992). In addition, administration of CCK itself, or of a selective CCK-B receptor agonist, instead of naloxone, does not precipitate withdrawal in morphine-dependent animals (Maldo- nado et al, 1994; Pournaghash and Riley, 1991). Incidentally, these observations are consistent with the suggestion that independent mechanisms mediate opioid tolerance and naloxone-precipitated withdrawal (Ling et al, 1984; Shen and Crain, 1992; see also Collin and Cesselin, 1991 and refs therein).

As for the question of the possible direct acute effects of opioids on CCKergic systems (see above), data concerning the effects of long-term opioid receptor stimulation on CCKergic neuro- transmission are still scarce. Indeed, it remains to be unambiguously demonstrated that there is actually a compensatory increase in the activity of some CCKergic neurones which would contribute to tolerance following chronic morphine administration. Thus, in rats, Pohl et a1 (1992) found that neither acute nor repeated morphine treatment affected the levels of CCK and of its encoding &A in various brain areas. With regard to acute morphine treatment, similar results have been reported by Rosen and Brodin (1989). At least in the cerebral cortex, CCK receptor binding characteristics also did not differ from control values in the phases of analgesia, tolerance, abstinence or withdrawal in rats which had been implanted with a miniosmotic pump to deliver morphine (Welin et at, 1994). However, contradictory data have been published. Thus, other groups have reported that morphine, especially following repeated adminis-


tration, stimulates CCK biosynthesis in selective CNS regions, including the spinal cord, the brain stem and the hypothalamus (Ding and Bayer, 1993; Faris et al, 1986; Pu et a1, 1994a; Zhou et al, 1992). In addition, it was shown that cerebrospinal fluid levels of radioimmunoassayable CCK increased significantly in rats receiving morphine under conditions which induce tolerance (Watkins et al, 198.5~). The latter observations are congruent with the idea that repeated morphine administration elicits a compensatory enhancement in the synthesis andor release of CCK that may underlie the development of morphine tolerance.

CCK as an opioid-like peptide If, as discussed above, opioids can modulate CCKergic systems, the reverse is also true: the stimulation of CCK receptors is able in turn to affect opioid systems. In other words, there could be reciprocal modulations between CCK and opioid systems. Numerous observations support the idea that CCK can activate opioid systems. For instance, Clarke et a1 (1992) concluded that the effects of proglumide on the sural-gastrocnemius medialis reflex in the rabbit, which is tonically inhibited by endogenous opioid peptides, can be explained through a stimulatory influence of CCK on the release of opioids. CCK was also found to activate an opioid mechanism in the guinea pig ileum (Garzon et al, 1987). Perhaps more impor- tantly, it was shown that subcutaneously or icv administered CCK or CCK receptor agonists exert naloxone-reversible antinociceptive effects in the mouse (Barbaz et al, 1986; Derrien et al, 1993; Hong and Takemori, 1989; Kubota et al, 1985; Noble et al, 1993; Zetler, 1980). In the rat, by the same routes of administration or by the intrathecal route, CCK proved to be an antinociceptive compound in the paw pressure and writhing tests, but not in the tail flick test (Gericke et al, 1990; Hill et al, 1987; Pittaway et al, 1987). However, when administered into the periaqueductal gray matter, CCK had an analgesic action in the tail flick test in this species (Jurna and Zetler, 1981). In addition, CCK has been reported to potentiate morphine antinociception (Pittaway and Hill, 1987). Finally, in apparent contradiction with the above-men- tioned hypothesis of a pronociceptive effect of CCK in animal models of neuropathic pain, Ros- sitch et a1 (1987) found that intraventricular administration of CCK attenuates scratching and biting due to dorsal root ganglionectomy in rats.

Variable results have been obtained with CCK receptor antagonists. Thus, whereas proglumide has been reported to have no effect on morphine

antinociception in the mouse’ hot plate test (Pitt- away and Hill, 1987), devazepide was shown to be able to antagonize morphine antinociception when administered icv to mice (Marrama et al, 1989, Poggioli et al, 1991). The latter effect was attributed to alterations in opioid receptors. Indeed, a significant reduction in the number of [3H]naloxone binding sites has been found in the brain stem of devazepide-treated mice (Marrama et al, 1989; Poggioli et al, 1991).

It should be emphasized that the analgesic effects of CCK generally require higher doses than those which reverse the antinociceptive effects of opioids. Since low doses of CCK are “physiological” whereas high doses are “pharmacological”, it is generally accepted that analgesia due to a large dose of CCK is a pharmacological phenomenon whereas the blockade of opioid analgesia by small doses of the peptide may be physiologically rele- vant (Baber et al, 1989). In fact, dose-dependent biphasic effects of CCK have been reported for many experimental models (see eg Dourish et al, 1988b; Hendrie et al, 1989; Noble et al, 1993; O‘Neil et al, 1989; Watkins et al, 1984, 1985a, b, and discussion in Baber et al, 1989), and the bell- shaped dose-response curves obtained with CCK- related compounds may also be explained through the differential effects of CCK-A and CCK-B receptor activation on endogenous opioid systems. In particular, Derrien et a1 (1993) showed that CCK-A but not CCK-B receptor stimulation induces endogenous opioid-dependent antinociceptive effects. This observation and others (Noble et al, 1994; Ossipov et al, 1994) have led to the proposal that activation of CCK-A receptors enhances the release of endogenous enkephalins, while the reverse situation occurs upon stimulation of CCK-B receptors.

The recent observation that CCK receptor agonists can block the jumping behaviour precipitated in mice by naloxone following a single dose of morphine can also be interpreted by an activation of endogenous opioid systems through CCK receptor stimulation (Malinge et al, in press). Interest- ingly, it has been established that exogenous CCK can actually increase the spinal release of met- enkephalin (Cesselin et al, 1984), and that endogenous CCK appears to exert a tonic stimulatory influence on spinal enkephalinergic neurones through the activation of CCK-A receptors (Beno- lie1 et al, unpublished data).

Congruent with the hypothesis that CCK can modulate the opioid systems through activation of (at least) two receptor types with opposite consequences (CCK-A agonists having excitatory

420 F Cesselin

effects), it was recently shown that CCK can prevent tolerance to the antinociceptive effects of morphine (Rezayat et al, 1994), via a probable action at CCK-A receptors, since the unsulfated form of the octapeptide does not affect the development of tolerance. This result was not unex- pected, if one considers that CCK and opioid systems are mutually antagonistic. Indeed, the resulting effect of the stimulation of one of them always depends on the state of the other. Thus, activating endogenous opioid systems through CCK-A receptors would alter the balance between the two systems in disfavour of the anti-opioid action of CCK via CCK-B receptors, resulting in less tolerance to the opioid effects. Evidence for the existence of subtypes of CCK-B receptors has been provided (Derrien et al, 1994; Durieux et al, 1992; Jagerschmidt et al, 1994; Kaufmann et al, 1994), but their respective (possibly opposite) roles in the modulation of opioid systems remain to be investigated.

Sites and mechanisms of CCWopioid interactions The localization of CCK neurones and receptors in the sensory cortex, PAG, thalamus, limbic struc- tures and spinal cord (Beinfeld et al, 1981; Hill et al, 1988) (where opioid systems are also present [see above] and where CCK and endomorphins can even coexist in the same neurones [Gall et al, 1987; Liu et al, 1994]), suggests that the phannac- ological and physiological effects of CCK in nociception can be due, at least in part, to its influence on both sensory and affective components of pain.

The results of numerous studies favour the idea that the site of interaction between CCK and opioids may lie in the spinal cord. At this level, the anti-opioid effect of CCK could be selective for p- and K-, but not 6, opioid analgesia (Magnuson et al, 1990; Wang et al, 1990). However, Wiertelak et a1 (1994) recently showed that conditioned anti- analgesia, which is very likely mediated at the spinal level by CCKergic systems (see above), abolishes conditioned analgesia triggered through not only p but also 6 opioid receptor activation.

If the dorsal horn of the spinal cord is very likeky one of the major sites of CCWopioid interactions in rodents, other areas involved in nociception must also be considered. Thus, CCK administered into the nucleus accumbens antagonizes the analgesic effect of systemic morphine in rats. Con- versely, morphine analgesia is markedly potentiated by intra-nucleus accumbens infusion of a CCK-B receptor antagonist (Pu et al, 1994b). Also in the PAG, infusion of CCK blocks morphine- and electroacupuncture-induced analgesia in the

rat (Chen et al, 1994; Li and Han, 1989), while local infusion of the non-selective CCK antagonist proglumide enhances the antinociceptive action of morphine (Watkins et al, 1985b).

The hypothesis of CCWopioid interactions in the context of a feedback loop composed of two reciprocal antagonist systems (fig 5 ) does not exclude that these interactions may involve events beyond receptor stimulation or blockade, provided both opioid and CCK receptors, which belong to the superfamily of G protein-coupled receptors, are located on the same targets. Such a colocalization occurs notably in the spinal cord of several species, at least on the terminals of primary afferent fibres (Ghilardi et al, 1992). In addition, CCK actually appeared to be able to affect opioid binding to brain membranes. For instance, by acting at its own receptors, CCK reduces [3H]etorphine binding to opioid receptors (Wang et al, 1989), and more specifically to p and K, but not 6, binding sites in the rat brain (Wang and Han, 1990). In vitro experiments with hippocampal slices suggest that an allosteric interaction occurs between the opioid and CCK-B receptors, in which the confor- mational state of the opioid receptor could be mod- ified (Miller and Lupica, 1994). It has even been suggested that CCK and opioid receptors in fact belong to the same complex (Hudson et a1, 1992).

Interaction between opioid and CCK receptors might also involve some intermediate component of a signal transduction cascade that is coupled to different effector mechanisms. For instance CCK and opioid receptors might act through the same G protein(s). It was suggested that CCK and opioids decrease and increase, respectively, K+ conduc- tance, via separate K+ channels located on the same neurone (Dourish, 1991). Others have proposed that, while opioid ligands reduce free intracellular calcium by blocking voltage-dependent Ca2+ influx, the anti-opioid effect of CCK could be associated with the mobilization of Ca2+ from intracellular stores (Wang et al, 1992).

The potential therapeutic use of CCK-related drugs for pain treatment Systemic proglumide has been found to potentiate morphine-induced analgesia in humans (Lavigne et al, 1989; Price et al, 1985). In line with the experimental findings showing that the effects of devazepide and L-365,260 on morphine antinociception depend on the rat’s response to a new environment or to the stress induced by an unac- customed experimental paradigm (Lavigne et al, 1992), proglumide appeared to enhance the analgesic effect of morphine for the postoperative


period only in non-sedated patients (Lavigne et al, 1989), but not in sedated patients using a con- trolled analgesia paradigm to manage their postoperative pain (Lehmann et al, 1989). With regard to the possible long-term clinical use of CCK receptor antagonists as an adjunct to opioid therapy, it is important to note that the CCK-A receptor antagonist devazepide does not enhance morphine- induced respiratory depression or constipation in the squirrel monkey (Dourish et al, 1990b). Fur- thermore, this compound has been reported to block the acquisition of morphine conditioned place preference in rats (Higgins et al, 1992). By contrast, the CCK-B antagonist L-365,260, in addition to potentiating the analgesic properties of morphine and reducing tolerance to the alkaloid, was shown to enhance the rewarding properties of the drug in the place preference test (Higgins et ul, 1992). This was considered as an important limita- tion in the possible therapeutic use of the association of CCK-B antagonist and exogenous opioids. Fortunately, this fear was allayed by subsequent studies which demonstrated that the potentiation of morphine-induced behaviour by L-365,260 does not extend to other paradigms. Indeed, neither this compound nor other CCK-A or CCK-B antagonists potentiate the subjective effects of opioids in a morphine drug discrimination paradigm and a model of heroin self-administration (Higgins et ~1,1994; Jackson et al, 1994). However, another caveat could emerge, which suggests that CCK antagonists should nevertheless be used with cau- tion in the management of chronic pain in man. Indeed, a chronic treatment with proglumide or lorglumide may no longer facilitate, and may even attenuate, opioid-induced antinociception in rats (Kellstein and Mayer, 1990).

Neuropeptide FF

Introduction The peptide Phe-Met-Arg-Phe-NH, JFMRFamide) was originally isolated from ganglia of the clam Macrocallista nimbosa (Price and Greenberg, 1977). FMRFamide-like immunoreactive material was subsequently detected in the nervous system of various invertebrates and vertebrates (Boer et at , 1980; Galabov, 1991). In particular, two FMRFamide-like peptides were isolated and sequenced from the bovine brain: an octapeptide, FLFQPQFWamide (F8Fa, or morphine-modulating peptide, now called neuropeptide FF [NPFF, table I]), and an octadecapeptide (A18Fa, NPAF) (Yang et al, 1985b). The structure of the precursor protein of these peptides is not yet known.

The presence of NPFF- and NPAF-related peptides in the brain and spinal cord of rat, mouse, guinea pig, pig and man has been established by several groups (Allard et al, 1991; Holmes and Dockray, 1989; Kivipelto and Panula, 1991; Kivi- pelto et al, 1989; Majane et al, 1988, 1989). NPFF immunoreactivity has notably been described in the rat CNS, with the highest concentrations in the spinal cord, hypothalamus, pons-medulla and neural lobe of the pituitary (Allard et al, 1991; Kivi- pelto and Panula, 1991; Majane et al, 1989). NPFF-containing cells are located within two main areas in the rat brain: the medial hypothalamus and the nucleus tractus solitarius (Lee et al, 1993).

Functional NPFF receptors were first observed in electrophysiological studies using cultured mouse spinal cord neurones (Guzman et al, 1989). Subsequently, specific binding sites for NPFF were characterized in the rat CNS, with a distribution different from that of opioid receptors. The highest densities of NPFF specific binding sites are found in the spinal cord, PAG, thalamus, amygdala and lateral septum (Allard et al, 1989, 1992). NPFF binding sites have also been identified in the human spinal cord (Allard et ul, 1994).

Initially, NPFF receptors were labelled with a tyrosyl derivative of NPFF ([*25I]YLFQPQRFa- mide, Allard et al, 1989, 1992), but new analogues of NPFF or FMRFamide, resistant to degradation, and with high affinity for NPFF receptors, are now available for binding and behavioural studies (Devillers et at, 1994; Gicquel et at, 1992; Malin et al, 1993b, c). Opioid ligands do not affect the specific binding of iodinated NPFF analogues to rat spinal cord membranes (Allard et al, 1989; Devillers et al, 1994) and, reciprocally, FRMFa- mide and NPFF-related peptides do not display significant affinity at opioid receptors in rat or guinea-pig brain membranes (Raffa et al, 1994). NPFF receptors are coupled to G proteins (Devill- ers et al, 1994; Payza and Yang, 1993; Payza et al, 1993).

Anti-opioid effects of FMRFamide, NPFF and related peptides Behavioural studies have shown that NPFF and NPFA decrease tail-flick latency, as expected from a hyperalgesic action, in rats (Yang el at, 1985b). In addition, FMRFamide, NPFF and their analogues can attenuate exogenous opioid-induced analgesia as well as stress- and defeat-induced analgesia (which is thought to be due, in part, to the triggering of endogenous opioid systems) in rodents (Brussaard et al, 1989; Kavaliers, 1987a, 1990; Kavaliers and Hirst, 1985b, 1986b; Kavali-

422 F Cesselin

ers and Innes, 1992a; Kavaliers and Yang, 1991; Million et al, 1993; Oberling et al, 1993; Raffa, 1988; Tang et al, 1984b; Yang et al, 1985b). In line with these behavioural data, in vivo electrophysiological studies indicate that NPFF can attenuate the inhibitory effects of p opioid agonists (but not those of 6 agonists) on C-fibre-evoked responses in nociceptive neurones in the rat dorsal horn (Magnuson et al, 1990).

In addition to reducing opioid-induced analgesia, FMRFamide- and NPFF-related peptides were found to attenuate other opioid responses. For instance, these peptides suppress opioid-induced feeding (Kavaliers and Hirst, 1985a, 1986a), morphine-induced inhibition of electrically provoked contractions of the guinea pig ileum (Demichel et al, 1993), and morphine-induced increases in locomotor activity (Marco et al, 1995; Raffa, 1989).

Intraventricular or intrathecal injection of immunoglobulin Gs raised against FMRFamide or NPFF produces, by itself, antinociception, and augments morphine- and stress-induced analgesia (Kavaliers and Innes, 1992a; Kavaliers and Yang, 1989, 1991; Tang et al, 1984b; Yang et al, 1985b).

There is also evidence that NPFF is involved in opioid tolerance and dependence. When injected into the third ventricle of morphine-tolerant and -dependent rats, anti-NPFF immunoglobulin Gs or a putative NPFF antagonist peptide reverse tolerance and attenuate the naloxone-induced withdrawal syndrome (Lake et al, 1991, 1992; Malin et at, 1990b, 1991). In contrast, NPFF or analogues injected into the third ventricle or subcutaneously precipitate the opioid abstinence syndrome in morphine-dependent rats (Malin et al, 1990a, 1993a, b, c). This is not due to alterations in NPFF binding characteristics since chronic morphine treatment alters neither the affinity, nor the number or G protein coupling of NPFF receptors in the rat CNS (Payza ef al, 1993). Interestingly, at higher doses, NPFF can cause a quasi-abstinence syndrome in normal (non-dependent) rats (Malin et al, 1990a).

From these data, it appears that NPFF not only counteracts exogenous and endogenous opioid analgesia (like CCK) but, in itself, can also exert a hyperalgesic action. In fact, this peptide seems to be involved not only in opioid tolerance (like CCK), but also in dependence. At odds with what was observed for spinal CCKergic systems, spinal NPFF systems do not seem to be involved in conditioned anti-analgesia (see above), since intrathecal administration of an anti-NPFF antiserum does not affect this process (Wiertelak et al, 1994).

The general scheme of such anti-opioid actions

OPlOlDS 7 NPFF

Receptors 2 ?

Receptors 1 ?

EFFECTS Fig 6. Schematic representation of NF'FF/opioid interactions. Opioids, either exogenous or endogenous, could activate NPFFergic systems, and the resulting enhanced release of NPFF could trigger anti-opioid actions. In turn, NF'FF, or exogenous agonists, could increase the release of endogenous opioid peptides and facilitate opioid-mediated effects. By analogy with CCK (see fig 5). one could hypothesize that NPFF exerts its anti-opioid effects through type 1 receptors, and its excitatory influence on opioidergic systems through type 2 receptors.

implies that exogenous and endogenous opioids should be able to activate NPFF systems (fig 6). Indeed, the spinal release of NPFF or FMRFa- mide-like material (see Devillers and Simonnet, 1994; Devillers et al, 1995; Simonnet e f al, 1994; Tang et al , 1984b; Zhu et al , 1992) can be enhanced by morphine in rats (Simonnet et al, 1994; Tang et al, 1984b). In the same species, administration of heroin has been shown to reduce NPFF levels in the spinal cord, as expected from an increased release of the peptide (Simonnet et al, 1994). This idea is supported by the observation that naloxone not only reverses heroin-induced analgesia but also induces a clear hyperalgesia, which can be attributed to the enhanced extracellular levels of the pronociceptive peptide NPFF provoked by heroin (Simonnet et al, 1994). Finally, Malin et a1 (1990b) reported that NPFF levels in the cerebrospinal fluid are markedly increased in opioid-tolerant and -dependent rats, further sup- porting the hypothesis that opioid/NPFF equilibrium may be involved in opioid tolerance and dependence.

Opioid-like effects of FMRFamide, NPFF and related peptides Among the NPFF analogues with high affinity for NPFF receptors synthesized by Gicquel et a1 (1992), some behave as NPFF, ie have hyperalgesic effects and inhibit morphine analgesia, whereas others exhibit significant analgesic properties and increase morphine analgesia (Gicquel et


al, 1992). Although the latter compounds could act as antagonists at NPFF receptors, several observations suggest that their opioid-like properties are due to other mechanisms. Indeed, the analgesic effects of these NPFF-related compounds can be blocked by naloxone (Gicquel et al, 1992). Fur- thermore, NPFF itself, FMRFamide, and related peptides, when administered intrathecally or supraspinally, can exert naloxone-sensitive antinociceptive effects against thermal and mechanical stimuli in the rat and the mouse (Gouardbres et al, 1993; Hill et al, 1987; Raffa and Connelly, 1992). In addition, by the intrathecal route, NPFF, at a sub-analgesic dose, has been shown to potentiate the analgesic effect of morphine (Gouardbres et al, 1993).

In fact, careful examination of the influence of NPFF on nociception revealed that the peptide's action is biphasic. Thus, in rats, icv administration of NPFF induces a rapid and short-lasting hyperesthesic effect, followed, during the night but not the day, by a long-lasting analgesic effect, the magnitude of which being related to the magnitude of the hyperesthesic effect (Oberling et al, 1993). The analgesic rebound could result from the triggering of endogenous opioid systems, which are known to be more active during the night in rodents (Naber et al, 1981; Wesche and Frederickson, 1979). This is congruent with the observations that NPFF effects on nociception and opioid withdrawal are more easily observed during the dark phase (Kava- liers, 1990; Malin et at, 1990a). However, the ability of NPFF-related peptides to enhance the release of endogenous opioids remains to be directly established.

Whatever their direction, the effects of NPFF are obtained when the peptide is injected in the third ventricle, but not in the lateral ventricles. This suggests that one site of action of NPFF for modulating nociception could be the PAC, which is rich i n NPFF receptors (AUard et al, 1992) and is immedi- ately adjacent to the third ventricle. Similarly, NPFF produces withdrawal signs only when administered in the third ventricle, but not in the lateral ventricle or intrathecally (Rothman et al, 1993). Obviously, these observations do not exclude that NPFF and opioids can also interact at the level of the spinal cord (see eg Tang el al, 1984b).

Other naloxone-reversible opioid-like effects of Fh4RFamide or NPFF have been reported. These include actions of these peptides on colonic bead expulsion in mice, intestinal myoelectrical activity (Million et al, 1993), heart rate and blood pressure in rats (Raffa, 1988; Raffa and Jacoby, 1989; Raffa et al, 1992; Wong et al, 1985).

The fact that the opioid antagonistic activity of an analogue of FMRFamide is displayed at lower doses than its opioid-like activity (which is remi- niscent of what is observed for CCK, see above), led Raffa and Connelly (1992) to suggest that the analgesic effects of this compound may be due to a weak agonistic activity at opioid receptors. How- ever, this hypothesis is not applicable to the opioid-like activity of the other FMRFamide- and NPFF-related peptides, since they have a very low affinity for opioid receptors (see above). In fact, as established for CCK, there could be two types of NPFF receptors, the stimulation of which would lead to opposite effects on opioid systems (see fig 6). This hypothesis is substantiated by the observation that NPFF has a multiphasic effect on the electrical activity of cultured mouse spinal cord neurones (Guzman et al, 1989). Furthermore, two receptors with different affinities for Fh4RFa- mide have already been described in the snail Helix aspersa (Payza, 1987).

Conclusion (fig 6) Thus, as with CCK and opioid systems, NPFF and opioid systems could constitute two physiologically coupled systems, each controlling the activity of the other, with NPFF exhibiting anti-opioid effects via the activation of one type of NPFF receptor, and an opioid-like action due to the triggering of endogenous opioid systems through the activation of another NPFF receptor type.

There is presently a lack of potent and selective NPFF receptor antagonists, which could be potential adjuncts to morphine for alleviating pain in humans or as a treatment medication for opioid abuse. However, it must be taken into account that chronic manipulations of NPFF systems could alter the characteristics of the opioid systems. In particular, chronic icv administration of anti-NPFF IgG has been shown to upregulate y opioid receptors (Rothman et al, 1991), and, conversely, chronic icv infusion of NPFF downregulates these receptors in the rat brain (but this latter change does not seem to affect the acute antinociceptive effects of icv injected morphine) (Rothman et al, 1993).

MIF and related peptides (table I)

Introduction The C-terminal tripeptide of oxytocin (Pro-Leu- Gly-NH,) is a melanocyte inhibiting factor (MIF- 1) (Celis et al, 1971; Nair et al, 1971) with anti- opioid properties (Galina and Kastin, 1986, see below). The hypothalamus contains an exopepti-

424 F Cesselin

dase which can produce MIF-1 from oxytocin (Walter et al, 1979). Other peptides, structurally related to MIF-1, but which do not derive from oxytocin, also have anti-opioid properties. These peptides are Tyr-MIF- 1 (Tyr-Pro-Leu-Gly-NH2), and Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH,). Tyr- MIF- 1 has been isolated from bovine hypothalamus and human parietal cortex (Horvath and Kas- tin, 1989, 1990), and Tyr-W-MIF-1 from bovine hypothalamic tissue and human frontal cortex (Erchegyi et al, 1992; Hackler et al, 1993).

In contrast to CCK and NPFF, Tyr-MIF-1 and Tyr-W-MIF-1 (but not MIF-1 itself, Lucian0 et al, 1981) are able to interact with opioid receptors with a higher potency at p sites than at 6 and K sites (Zadina and Kastin, 1986; Zadina et al, 1992). Thus, Tyr-W-MIF-1 and Tyr-MIF-1 inhibit 50% of the specific binding of tritiated DAGO (a selective p agonist) to rat brain membranes at concentrations of 0.3 and 6.0 jM, respectively (Erche- gyi et al, 1992; Zadina and Kastin, 1986). How- ever, non-opioid specific binding sites for Tyr-MIF- 1 have been identified in brain (Zadina and Kastin, 1985; Zadina et al, 1982, 1989, 1990; Zhang et at, 1992). The affhity of Tyr-MIF-1 for these sites is about 50-fold higher than for p opioid receptors. However, MIF-1 does not bind to these Tyr-MIF-1 specific sites (Zadina and Kastin, 1985; Zhang et al, 1992).

A fourth member of the MIF family has recently been isolated from human brain cortex, and named Tyr-K-MIF- 1 (Tyr-Pro-Ly s-Gl y -NH2) (Hackler et al, 1994, table I). Tyr-K-MIF-1 appears to bind to Tyr-MIF-1 specific sites and to its own sites. This peptide exhibits only a low activity on opioid binding (see Reed et al, 1994).

Anti-opioid properties of MIFs MIF- 1 and Tyr-MIF- 1 have been shown to reduce exogenous opioid-induced analgesia in rodents (in the tail flick and scratching tests, Datta et al, 1982; Kastin et al, 1979, 1980, 1984, 1985), goldfish (Ehrensing et al, 1982), and man (in the cold pres- sor test, Ehrensing et a l , 1984). MIF-1 also decreases opioid-induced ingestive behaviour (Kavaliers and Hirst, 1985c; Olson et al, 1980) and hypothermia (Yehuda et al, 1980).

Data also indicate that MIF-1 and Tyr-MIF-1 can reduce the effects of endogenous opioids. In particular, both peptides are able to inhibit the expression of some forms of stress-induced analgesia in various species (Galina and Kastin, 1985, 1987, 1988; Kavaliers, 1987b; Kavaliers and Hirst, 1986b, c; Kavaliers and Innes, 1992b; Krowicki, 1991a, b; Lipa et al, 1989).

That Tyr-MIF-1 activity might increase in response to chronic opioid administration has been proposed by Zadina et a1 (1989) to explain why prolonged, but not acute, exposure to morphine decreases the specific binding of Tyr-MIF- 1 to brain tissue. Such an increase in Tyr-MIF-1 activity could be involved in the behavioural expression of opioid withdrawal, since an icv injection of exogenous MIF- 1 has been reported to precipitate withdrawal signs in levorphanol dependent mice (Contreras and Takemori, 1984b). Similarly, Tyr- MIF-1 (protected from degradation by the peptidase inhibitor bestatin) triggers an abstinence syndrome in morphine-dependent rats, but not in opioid-naive animals when injected into the third venticle (Malin et al, 1993d). However, rather than favourizing tolerance, icv administered MIF- 1 can antagonize the development of tolerance to levorphanol in mice (Contreras and Takemori, 1984b).

Opioid-like actions of MIFs Similarly to CCK and NPFF, MIFs also exert some opioid-like actions. Thus, icv administration of Tyr-W-MIF- 1 induces a long-lasting naloxone- reversible analgesia in the tail-flick test in rats (Zadina et al, 1993). In addition, central or oral administration of Tyr-MIF- 1 modulates gastric emptying and gastrointestinal motility in a naloxone-reversible manner in rodents (Million et al, 1992, 1994; Zadina et al , 1992). Tyr-MIF-1- induced inhibition of contractions of the guinea pig ileum can be reversed by CTOP, a selective p opioid receptor antagonist, but not by a selective K antagonist, nor-binaltorphimine (Erchegyi et al, 1993).

Are MIFs partial agonists at opioid receptors? In the guinea-pig ileum, Tyr-MIF-1 and Tyr-W- MIF- 1 have both opioid agonistic and antagonistic activities. Thus, Tyr-MIF- 1 and Tyr-W-MIF- 1 exhibit agonist-like activity as shown by a dose- dependent inhibition of electrically induced contractions through a selective action at the p (but not 6 or K) opioid receptor (Erchegyi et al, 1993; Zadina and Kastin, 1986; Zadina et al, 1992). In contrast, the tetrapeptides can also attenuate the inhibition of contractions due to morphine and DAGO, especially in morphine-tolerant animals and in preparations of ileum pretreated with the opioid alkylating agent, P-chlornaltrexamine (Erchegyi et al, 1992; Zadina et al, 1992). Without excluding the possibility that MIFs (especially Tyr-MIF- 1) may exert their anti-opioid properties through their own high affinity binding sites, altogether these data suggest that the antagonistic


OPlOlDS MIFs

Opioid receptors I

P EFFECTS

Fig 7. Schematic representation of the interactions between the peptides of the MIF family and the opioids. Although specific binding sites exist for Tyr-h4IF-1 in the brain, through which this peptide could exert an anti-opioid effect, thepeptides of the MLF family could also act directly at opioid receptors where they behave as antagonists at low concentrations and as agonists at high concentrations.

action of these compounds would rather result from their “partial agonistic” properties at p opioid receptors (fig 7). The fact that antagonistic properties are best observed under conditions of reduced receptor reserve would appear to be consistent with an efficacy of MIFs at the p receptors low enough to block the action of other opioid ligands. Indeed, agonists with relatively low efficacy are known to become antagonists when the efficiency of the stimulus-response coupling is reduced (see Kenakin, 1987).

CONCLUSION (fig 8)

The data summarized in this review initially led to the concept of “anti-opioid” peptides on the basis of extensive clinical and fundamental studies, which were carried out in order to elucidate the mechanisms of tolerance and dependence to opioids. In fact, the three peptides which have been reviewed in this article, CCK, NPFF and MIFs, have both anti-opioid and opioid-like properties, such that it would be more appropriate to refer to them as “opioid modulating” peptides (the label initially given to NPFF) than “anti-opioid” peptides. With regard to the models which tend to explain opioid tolerance and dependence only by

- * + 1

\/ + - RESULTING EFFECT

Fig 8. Homeostatic mechanism implying two mutually “antagonistic” substances, able to reciprocally stimulate their production andor release. “A” enhances the release and reduces the effects of “B”, and reciprocally “B” modulates the release and effects of “A”, such that the value of a given parameter affected in opposite directions by A and B is the result of the dynamic equilibrium between the two systems, A and B.

alterations affecting opioid receptors themselves, and/or the transducers and effectors to which they are coupled (see Collin and Cesselin, 1991), the concept of anti-opioid peptides has the advantage of explaining why opioid receptors remain functional following chronic exposure to opioids, since their blockade with an antagonist results in a withdrawal syndrome (whereas this blockade is without effect in normal man or animal). In fact, the multiple feed-back loops within a system or between systems, as they appear in the figures illustrated in this paper (see figs 4-7), do not constitute a peculiar originality. They have to be considered in the general context of homeostasis, ie the coordinated reactions which maintain most of the biological dynamic equilibria (fig 8).

ACKNOWLEDGMENTS

The author is indebted to Drs M Hamon and I Nevo for their critical reading of the manuscript.

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Opioid and anti-opioid peptides