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Secondly, it is clear that the clinical research standards for exper-mental bias reduction and transparent methodology reporting areot generally evident in pre-clinical research across most therapeu-ic areas, including pain. There is evidence that when bias reducing

ethods are not used, or at least not reported, in pre-clinical stud-es there is an overestimation of the efficacy of novel drugs. Theonsiderable advances which have been made in this regard in thetroke field will be reviewed and the case for adopting their “Goodaboratory Practice” standards for mitigation of experimental biasn animal studies of pain will be argued. Furthermore, adoptionf the recently published, CONSORT-equivalent, ARRIVE report-ng format for animal studies will increase not only the readersbility to ascertain the methodological quality of studies, but alsompower systematic reviews of the pre-clinical literature.

Funding: Wellcome Trust (London Pain Consortium), Innova-ive Medicines Initiative – EUROPAIN (European Commission andelected EFPIA members) and Derek Butler Trust.

ecommended reading

[1] Rice ASC. Predicting analgesic efficacy from animal models of peripheral neu-ropathy and nerve injury: a critical view from the clinic. In: Mogil JS, editor.Pain 2010—an updated review: refresher course syllabus. Seattle: IASP Press;2010. p. 415–426.

[2] Andrews N, et al. Spontaneous burrowing behaviour in the rat is reduced byperipheral nerve injury or inflammation associated pain. European Journal ofPain 2012;16:485–95.

[3] Hasnie FS, et al. Further characterization of a rat model of varicella zostervirus-associated pain: relationship between mechanical hypersensitivity andanxiety-related behavior, and the influence of analgesic drugs. Neuroscience2007;144(4):1495–508.

[4] Wallace VCJ, et al. Anxiety-like behaviour is attenuated by gabapentin, mor-phine and diazepam in a rodent model of HIV anti-retroviral-associatedneuropathic pain. Neuroscience Letters 2008;448(1):153–6.

[5] Wallace VCJ, et al. Characterisation of rodent models of HIV-gp120 and anti-retroviral associated neuropathic pain. Brain 2007;130(10):2688–702.

[6] Wallace VCJ, et al. Pharmacological, behavioural and mechanistic analysis ofHIV-1 gp120 induced painful neuropathy. Pain 2007;133(1–3):47–63.

[7] Sena ES, et al. How can we improve the pre-clinical development of drugs forstroke? Trends in Neurosciences 2007;30(9):433–9.

[8] Sena ES, et al. Publication bias in reports of animal stroke studies leads to majoroverstatement of efficacy. PLoS Biology 2010;8(3):e1000344.

[9] Rice ASC, et al. Animal models and the prediction of efficacy in clinical trials ofanalgesic drugs: a critical appraisal and call for uniform reporting standards.Pain 2008;139(2):243–7.

10] Macleod MM, et al. Good laboratory practice. Preventing introduction of biasat the bench. Stroke 2009;40(3):e50–2.

11] Kilkenny C, et al. Improving bioscience research reporting: the ARRIVE guide-lines for reporting animal research. PLoS Biology 2010;8(6):e1000412.

ttp://dx.doi.org/10.1016/j.sjpain.2012.05.003

valuating pain-related behavior in spinal cord injury

athrine Baastrup

Danish Pain Research Center, Aarhus University Hospital, Aarhus,enmark

The spinal cord contusion (SCC) model has been shown to haveigh mechanistic face validity to a traumatic spinal cord injurySCI). With the SCC model the majority animals consistently displayong-lasting mechanical hypersensitivity to thoracic stimulation,.e. corresponding to the at-level area. In the talk, the followingopics will be discussed and relevant results obtained with rats inhe spinal cord contusion model will be presented:

The simple paw withdrawal response to stimulation remains afrequently applied method in preclinical pain research despite

the acknowledged limitations in validity and predictability. Theuse of methods relying on paw withdrawal, which is a spinalreflex, is particularly problematic in models of SCI due to thedevelopment of the spastic syndrome.

of Pain 3 (2012) 173–198

• Development of methods that require cortical involvement mayincrease the predictability of preclinical research. One suchmethod, the place escape avoidance paradigm, has been inves-tigated as an outcome measure of evoked pain after SCI. Themethod relies on the rats’ natural avoidance of brightly lid areas.

• Measures of pain-related behavior such as anxiety- anddepression-like behavior, both known comorbidities of pain, maybe indirect indications of spontaneous pain, but this behavior hasnot been consistently reproduced in the spinal cord injury model.One method is the elevated plus maze, which is suggested toreflect predator avoidance behavior (e.g. avoidance of open arms).

• Experiments with the relatively new and ethologically relevantoutcome measure ‘burrowing’ has been performed to investigateif this assay reflects a form of rodent “quality of life”, or if it maybe a more specific measure of pain-related affect.

• Finally, some of the challenges regarding possible experimentalbiases will be mentioned in relation to the spinal cord contusionmodel and the applied outcome measures.

Funding: This work is part of the Innovative Medicine Initia-tive EUROPAIN, www.imi.europa.eu. Further support was receivedfrom the Velux Foundation.

http://dx.doi.org/10.1016/j.sjpain.2012.05.004

The role of the amygdala in sensory and emotional-like painbehavior in neuropathic animals

Antti Pertovaara

Institute of Biomedicine/Physiology, University of Helsinki, Finland

The amygdala is a major player in emotions, and it has reciprocalconnections with structures involved in pain modulation. Stimula-tion and lesion studies indicate that the amygdala has a dual role inpain modulation. Recent studies indicate that peripheral neuropa-thy induces neural plasticity in the amygdala, which is the topicof this review. Following peripheral nerve injury, increased post-synaptic currents evoked by ascending inputs and generation ofnew neurons have been demonstrated in the amygdala. Periph-eral nerve injury has also influenced the pain-regulatory role ofthe amygdala as shown by the amygdala-induced suppression ofcoeruleospinal pain-inhibitory pathways. In neuropathy, amyg-daloid type I glutamatergic metabotropic receptors have enhancedpronociceptive action on pain-regulatory cells in the rostroventro-medial medulla and affective-like as well as sensory-discriminativepain behavior. Moreover, endogenous corticotropin-releasing fac-tor in the amygdala of neuropathic animals had differential effectson sensory and emotional aspects of pain. Together these find-ings indicate that peripheral neuropathy induces functional andanatomical changes in the amygdala that influence affective-likeand sensory pain behavior.

http://dx.doi.org/10.1016/j.sjpain.2012.05.005

Peripheral and central pain mechanisms—From animal modelsto clinical research

Johannes Gjerstad

National Institute of Occupational Health, University of Oslo, Norway

Long-lasting pain is often a more serious problem than the initialinjury or disease that initiated it. However, the neuronal mecha-

nisms underlying development of chronic pain is complex, and notwell understood.

The first part of the presentation addresses how the mecha-nisms underlying persistent pain may be investigated in animal

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odels. In particular the role of central sensitization, i.e. induc-ion and maintenance of spinal LTP, will be emphasised. Data fromur ongoing research based on electrophysiological methods, q PCRnd PET brain imaging, will be shown. Studies of changes in spinaleuronal excitability and gene expression, as well as changes ineuronal activity in the brain, will be presented.

In the second part of the talk the animal data will be followed-p with clinical data from our ongoing research in patients with

ong-lasting low back pain and sciatica. Based on findings from thenimal experiments, the neuronal events after disc herniation inatients with persistent pain will be discussed. This part of theresentation will also address how genetic susceptibility may con-ribute to development of long-lasting low back pain and sciatica.

It is concluded that translation of knowledge from basic neuro-cience into clinical research as discussed here may be importantor future understanding of long-lasting pain states.

ecommended reading

1] Jacobsen LM, Iordanova E, Storesund A, Pedersen LM, Rygh LJ, Røe C, et al. TheCOMT rs4680 met-allele contributes to long lasting low back pain, sciatica anddisability after lumbar disc herniation. European Journal of Pain 2012 [Epubahead of print].

2] Pedersen LM, Jacobsen LM, Mollerup S, Gjerstad J. Spinal cord long-term poten-tiation (LTP) involves increased spinal gene expression of IL-1�, GDNF and iNos.European Journal of Pain 2010;14:255–60.

3] Hjørnevik T, Jacobsen LM, Qu H, Bjaalie JG, Gjerstad J, Willoch F. Metabolic plas-ticity in supraspinal pain modulating circuitry after noxious spinal LTP. Pain2008;140:456.

ttp://dx.doi.org/10.1016/j.sjpain.2012.05.006

uman experimental models of central sensitization—Do theyridge the gap between animal models and clinical observa-ions?

le Kæseler Andersen

Integrative Neuroscience group, Center for Sensory-Motor Interaction,alborg University, Denmark

Human experimental models of pain involve two separateopics: Standardised activation of the nociceptive system and

easurement of the evoked responses (psychophysics, elec-rophysiology, autonomic responses, imaging techniques). Theltimate goal of advanced human experimental pain research

s to obtain a better understanding of mechanisms involved inain transduction, transmission and perception under normal andathophysiological conditions. It has for a long time been arguedhat human experimental pain research bridges the gab betweenasic animal studies and clinical observations. How well that notionolds for models of central sensitisation will be discussed in thisalk. The primary advantages of experimental assessment of painensitivity are claimed to be:

Stimulus intensity, duration and modality are controlled and notvarying over time in contrast to studies in patients,The ultimate end-point, pain can be assessed in humans oppositeto studies in animals,Experimental models of pathological conditions can be studiedleading to a better understanding of the underlying mechanisms.

This talk will discuss how well the human models of central sen-itisation actually work. This will include a survey of the existingodels and a discussion of how well the sensory characteristics

eflect findings in both animals and patients. Moreover, the out-ome measures available for human experimental pain researchill be discussed in terms of sensitivity and reliability in relation

o assessment of central sensitisation. The talk will focus on stud-[

of Pain 3 (2012) 173–198 175

ies related to models of central sensitisation at spinal level. Thiswill include models using electrical stimulations for induction oflong term potentiation and models involving injection (intrader-mal/intramuscular) of algogenic substances. Outcome measureswill include the nociceptive withdrawal reflexes for probing spinalexcitability, techniques for assessing vascular responses (imaging),and advanced psychophysical assessments.

http://dx.doi.org/10.1016/j.sjpain.2012.05.007

Assessment of central sensitization in the clinic. Is it possible?

Per Hansson

Dept of Molecular Medicine and Surgery, Karolinska Institutet andDept of Anaesthesiology and Intensive Care, Karolinska University Hos-pital, Stockholm, Sweden

Central sensitization, a wording derived from the animal neu-rophysiological literature, is undoubtedly in fashion in the field ofpain medicine and is frequently articulated by clinical researcherswhen referring to any spread of pain-related sensitivity and isused by clinicians to explain strange clinical phenomenologies.In more strict neurophysiological terms central sensitization is aform of activity-dependent neuronal plasticity and has recentlybeen described regarding its highly complex cellular and molec-ular mechanisms [1] and potential implications for the diagnosisand treatment of pain [2].

Acquainting data from animal experiments on altered neuronalexcitability as a result of challenging input in nocieptive afferentswith the clinical literature on local/regional and remote hyper-sensitivity to normally non-painful and painful stimuli in patientswith localized pain conditions, non-critical interpretations of dataare commonly found in the latter [3,4]. The pre-clinical litera-ture on the subject offers insights into use-dependent synapticplasticity in dorsal horn neurons in or near the segment receiv-ing nociceptive input from the periphery. The clinical literaturedemonstrates local and remote widespread hypersensitivity in con-ditions with a fairly well understood pathophysiology (and in lesswell understood conditions) which frequently and indiscriminatelyis interpreted in terms of central sensitization. The presentationwill:

- draw attention to the mismatch between pre-clinical and clinicaldata on central sensitization,

- discuss suggested features of the clinical phenotype that may relyon homo- and heterotopic central sensitization,

- suggest exercising caution when interpreting clinical data interms of central sensitization,

- point to alternative explanations and nomenclature forwidespread increased sensitivity.

Currently, central sensitization lacks diagnostic criteria in theclinical scenario and should hence be employed warily, if at all,in such a setting. In the interest of pursuing a mechanism-basedclassification and treatment of pain translational aspects of painmedicine would benefit from more cautious interpretations of find-ings in human studies. Repeated use of an unproven concept hascaught on in the pain community and may leave translationalaspects of pain trivialized and us ridiculed by those who knowbetter.

References

1] Woolf CJ. Central sensitization: Implications for the diagnosis and treatment ofpain. Pain 2011;152:S2–15.