Pain consists of a sensory component (the detection and transmission of painful stimuli) and an affective component (the processing of emotional and behavioural responses). Writing inNeuron, Braz and colleagues show that different populations of nociceptors neurons that sense painful stimuli might engage parallel ascending pathways that target limbic (affective) and motor regions of the brain.Anociceptoris areceptorof asensory neuron(nerve cell) that responds to potentially damaging stimuli by sending signals to the spinal cord and brain. This process, callednociception, usually causes the perception ofpain.Nociception(alsonocioceptionornociperception) is the encoding and processing ofharmful stimuliin thenervous system,[1]and, therefore, the ability of a body to sense potential harm. It is theafferentactivity in theperipheralandcentral nervous systemsproduced by stimulation of specializedfree nerve endingscalled "nociceptors" or "pain receptors" that only respond to tissue damage caused by intense chemical (e.g., chilli powder in the eyes), mechanical (e.g., pinching, crushing) or thermal (heat and cold) stimulation.

Nociceptors were discovered byCharles Scott Sherringtonin 1906.

Origen embriologicoNociceptors develop fromneural creststem cells.Earlier forming cells from this region can become non-pain sensing receptors; eitherproprioceptorsor low-thresholdmechanoreceptors. All neurons derived from neural crest, including embryonic nociceptors, express the TrkA which is a receptor to nerve growth factor (NGF). However, transcription factors that determine the type of nociceptor remain unclearFollowing sensory neurogenesis, differentiation occurs and two different types of nociceptors are formed. They are classified as either peptidergic or nonpeptidergic nociceptors. The sets of receptors express distinct repertoires of ion channels and receptors. With their specialization, it allows the receptors to innervate different peripheral and central targets. This differentiation occurs in both perinatal and postnatal periods. The nonpeptidergic nociceptors switch off the TrkA and begin expressing Ret. Ret is a transmembrane signaling component which allows for the expression of another growth factorglial cell-derived growth factor (GDNF). This transition is assisted by Runx1 which has proven to be vital in the development of nonpeptidergic nociceptors. On the contrary, the peptidergic nociceptors continue to use TrkA and they express a completely different type of growth factor. Currently there is a lot of research being done to determine more specifically what creates the differences between nociceptorsLocalizacionExternal examples are intissuessuch asskin(cutaneous nociceptors),corneaandmucosa. Internal nociceptors are in a variety of organs, such as themuscle,joint,bladder,gutand continuing along the digestive tract. The cell bodies of these neurons are located in either thedorsal root gangliaor thetrigeminalganglia.[2]The trigeminal ganglia are specialized nerves for the face, whereas the dorsal root ganglia associate with the rest of the body. The axons extend into the peripheral nervous system and terminate in branches to form receptive fields.

Tipos y funciones

When the electrical energy reaches a threshold value, anaction potentialis induced and driven towards thecentral nervous system(CNS). This leads to the train of events that allows for the conscious awareness of pain. The sensory specificity of nociceptors is established by the high threshold only to particular features of stimuli.Only when the high threshold has been reached by either chemical, thermal, or mechanical environments are the nociceptors triggered. The majority of nociceptors are classified by which of the environmental modalities they respond to. Some nociceptors respond to more than one of these modalities and are consequently designated polymodal. Other nociceptors respond to none of these modalities (although they may respond to stimulation under conditions of inflammation) and are referred to as sleeping or silent.

Nociceptors have two different types of axons. The first are theA fiberaxons. They are myelinated and can allow an action potential to travel at a rate of about 20 meters/second towards the CNS. The other type is the more slowly conductingC fiberaxons. These only conduct at speeds of around 2 meters/second.[5]This is due to the light or non-myelination of the axon. As a result, pain comes in two phases. The first phase is mediated by the fast-conducting A fibers and the second part due to (Polymodal) C fibers. The pain associated with the A fibers can be associated to an initial extremely sharp pain. The second phase is a more prolonged and slightly less intense feeling of pain as a result of the damage. If there is massive or prolonged input to a C fiber, there is a progressive build up in the spinal cord dorsal horn; this phenomenon is similar totetanusin muscles but is calledwind-up. If wind-up occurs there is a probability of increased sensitivity to painVia

Transmission through the central nervous system[edit]Spinothalamic tract[edit]Before reaching the brain, the spinothalamic tract splits into the lateral, "neospinothalamic" tract and the medial, "paleospinothalamic" tract.[6]Neospinothalamic tract[edit]Fast pain travels via typeA fibersto terminate in thedorsal hornof the spinal cord where theysynapseondendritesof the neospinothalamic tract. Theaxonsof these neurons cross the midline (decussate) through theanterior white commissureand ascend contralaterally along theanterolateral system. These fibres terminate on theventrobasal complexof the thalamus and synapse with the dendrites of thesomatosensory cortex. Fast pain is felt within a tenth of a second of application of the pain stimulus and is a sharp, acute, prickling pain felt in response to mechanical and thermal stimulation. It can be localised easily if A fibres are stimulated together with tactile receptors.[citation needed]Paleospinothalamic tract[edit]Slow pain is transmitted via slower typeC fibersto laminae II and III of the dorsal horns, together known as thesubstantia gelatinosa. Impulses are then transmitted to nerve fibers that terminate in lamina V, also in the dorsal horn, synapsing with neurons that join fibers from the fast pathway, crossing to the opposite side via the anterior white commissure, and traveling upwards through the anterolateral pathway. These neurons terminate throughout thebrain stem, with one tenth of fibres stopping in thethalamusand the rest stopping in themedulla,ponsandperiaqueductal greyof themidbrain tectum.

Pain

Pain AfferentsPain afferents can bemyelinatedorunmyelinated. The unmyelinated pain fibers belong to the class of afferent fibers called theC fibersand conduct from about 0.5 to 2.0 meters/second. The myelinated pain afferents belong to the class of afferent axons termed theA-delta fibersand conduct action potentials between about 5 to 30 meters/sec. These are the smallest and slowest of the myelinated axons. (By contrast, myelinated axons for fine touch and proprioception conduct between 35 to 120 meters/sec.)A C fiber can respond to a broad range of painful stimuli, including mechanical, thermal or metabolic factors. The pain produced is slow, burning, and long lasting. The neurotranmitter in the dorsal horn isglutamatealong with certain peptides such assubstance P. The receptors for glutamate are not only fast, five subunit ligand gated ion channels, but alsoNMDA receptors. The latter do not open immediately, but only followingprolonged depolarization. Thus, continual stimulation of C fibers eventually causes greater excitation in the postsynaptic neurons in the dorsal horn as the NMDA receptors start adding to the response.An A-delta fiber responds to either mechanical stimuli or temperature stimuli in the painful realm and produces the acute sensation of sharp, bright pain. Their neurotransmitter in the dorsal horn isglutamateacting on fast, five subunit ligand gated ion channnels.The receptor for capsaicin, which is found in hot peppers, is located in the C fibers. This ion channel normally is opened by hot stimuli.C fibers, Substance P and InflammationInterestingly, the C fibers interact with the process of inflammation. Observe the figure below. The directions that action potentials conduct should seem quite surprising, because action potentials in certain branches of an afferent neuron aremoving peripherally!! The is called theaxon reflex. In this way, certain painful stimuli not only lead to the sensation of pain in the central nervous system, but also to the release of substance P locally. This increases inflammation by causing histamine release and dilation of blood vessels.

Reduction in the Perception of PainOne phenomenon you may have observed in yourself is that stimulation of touch sensors (A-beta fibers) in the skin by rubbing can disrupt the sensation of pain arising in a nearby structure such as a muscle. This is usually interpreted in terms of thegate control theory.Observe the figure of the dorsal horn, which shows that large, mechanically sensitive afferentsexcite interneuronsthat in turninhibitthe neurons that carry pain information from the dorsal horns to the brain. (Axons in the anterolateral tract project to the thalamus.)What physiological function this might serve is not clear, but it does help explain various phenomena that reduce pain. The effect oftranscutaneous electrical stimulation (TENS)presumably is due to this effect. In these devices, weak electrical current is applied to the skin near the site of pain (such as the lower back) in order to stimulate the A-beta fibers and reduce the flow of pain information to the brain.

Much more potent, however, is theanalgesiaproducted bymorphineand other relatedopiates. The opiates bind toopioid receptorsfound in many areas of the brain, but are especially concentrated in theperiaqueductal gray(ie; the area surrounding the cerebral aqueduct in the midbrain), themedullaand thedorsal horns. Infusion of morphine into the periaqueductal gray is especially effective in producing profound analgesia. This also is the area of the brain in which electrical stimulation produces a strong analgesic effect.Naturally, with such a potent effect, one suspects that the brain contains molecules that naturally activate the receptors that respond to the opiates. These molecules are termed theopioid peptides, and include theenkephalins,dynorphinandbeta-endorphin. Beta-endorphin is released by neurons with cell bodies in the hypothalamus and we won't consider this further.The enkephalins (and dynorphin) are found in the periaqueductal gray, the medulla and the dorsal horns. Observe the pathway to the left that descends from the periaqueductal gray via the medulla to the dorsal horns. This leads to the release from interneurons of enkephalins that inhibit the flow of pain information to the brain.

Neuropathic PainThe termneuropathic painrefers to pain that arises due toaltered neuronal propertiesrather than an actual painful stimulus. On the other hand,nocioceptive painrefers to pain that arises due to a painful stimulation of pain afferent neurons. A table on the handout under disorders compares the clinical presentation of the two. There is no need to memorize this table, but do become familiar with the terminology used.Consider these terms often connected to neuropathic pain:

What is meant byhyperalgesia?AnswerWhat is meant byallodynia?AnswerWhat is meant bylancinating?AnswerProlonged, chronic pain can lead to conditions in which the sensation of pain is heightened. Clinicians refer to the increased sensation of pain with time as"wind-up".One aspect of wind-up may be the steady release of substance P in the dorsal horns. Peptides are removed slowly and can diffuse around somewhat. The continued presence of substance P might lead to cellular changes such as increased neuronal sprouting. Other cellular changes might follow from activation of NMDA receptors. Recall that these only open with prolonged depolarization, such as would occur with prolonged pain. The resulting influx of Ca++ could activate enzymes (such as nitric oxide synthase) or trigger other long lasting cellular changes. But, whatever the case, the neurons are functionally and physically changed.Neuropathic pain can arise not only from painful stimuli acting on pain sensors but also from damaging or cutting nerves. In this category, we will discussphantom limb pain, which occurs in amputees, and the relateddeafferentation pain. A neuroma, for example, might create the conditions that lead to neuropathic pain.Sympathetically maintained painrefers, by definition, to neuropathic pain in which blocking the sympathetic nervous system helps relieve the pain. This is the case in various neuropathic pain situations. Apparently, there are interconnections between efferent sympathetic outflow and incoming afferent pain information. In addition to other types of pain medications, sympathetic ganglia may be blocked as well as circulating norepinephrine and epinephrine.A region with this type of pain might have altered skin blood flow,edema, or abnormal sweating. With time there may be increased hair and nail growth and eventually severe degenerative changes in the muscles and bones. It can spread out from its original region. These sorts of pain syndromes need to be treated, because after a few months they can become irreversible and very refractory to treatment.(The classification of neuropathic pain involving sympathetic effects is variable and confusing. But the term "complex regional pain syndrome" is the most common term that refers to the whole set of these types of pain syndromes.)