Terence J. Coderre

Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

&NA; Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral Neurol mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central Neurol function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central Neurol plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection.

Evidence is presented which suggests that central neural changes occur during the brief early phase after subcutaneous formalin injection that are essential for the expression of pain during the long-lasting (tonic) later phase. First, tonic pain responses to subcutaneous formalin injections are abolished only if the injected hindpaw is locally anesthetized at the time of injection as well as the time of testing (30-60 min later). Second, tonic formalin pain is substantially reduced by brief spinal anesthesia given 5 min before, but not 5 min after the formalin injection.

Central Neuroplasticity and Pathological Pain

Abstract: The traditional specificity theory of pain perception holds that pain involves a direct transmission system from somatic receptors to the brain. The amount of pain perceived, moreover, is assumed to be directly proportional to the extent of injury. Recent research, however, indicates far more complex mechanisms. Clinical and experimental evidence shows that noxious stimuli may sensitize central neural structures involved in pain perception. Salient clinical examples of these effects include amputees with pains in a phantom limb that are similar or identical to those felt in the limb before it was amputated, and patients after surgery who have benefited from preemptive analgesia which blocks the surgery‐induced afferent barrage and/or its central consequences. Experimental evidence of these changes is illustrated by the development of sensitization, wind‐up, or expansion of receptive fields of CNS neurons, as well as by the enhancement of flexion reflexes and the persistence of pain or hyperalgesia after inputs from injured tissues are blocked. It is clear from the material presented that the perception of pain does not simply involve a moment‐to‐moment analysis of afferent noxious input, but rather involves a dynamic process that is influenced by the effects of past experiences. Sensory stimuli act on neural systems that have been modified by past inputs, and the behavioral output is significantly influenced by the “memory” of these prior events. An increased understanding of the central changes induced by peripheral injury or noxious stimulation should lead to new and improved clinical treatment for the relief and prevention of pathological pain.

Deafferentation and chronic pain in animais: An evaluation of evidence suggesting autotomy is related to pain

&NA; This paper examines evidence which suggests that the self‐mutilation of deafferented limbs exhibited by laboratory animals is a response to pain or dysesthesia and is therefore an adequate model of chronic pain. Evidence from studies using physiological, pharmacological and behavioral methods provides strong support that autotomy reflects chronic pain. New evidence presented in this paper demonstrates that specific treatments can be used to manipulate the extent of autotomy, causing increases or decreases, as well as restricting it to specific parts of a denervated foot. This evidence argues that autotomy scores are an appropriate measure of the degree of pain or dysesthesia which results from the deafferentation of a limb.

Chronic post-ischemia pain (CPIP): a novel animal model of complex regional pain syndrome-type I (CRPS-I; reflex sympathetic dystrophy) produced by prolonged hindpaw ischemia and reperfusion in the rat.

Abstract A neuropathic‐like pain syndrome was produced in rats following prolonged hindpaw ischemia and reperfusion, creating an animal model of complex regional pain syndrome‐Type I (CRPS‐I; reflex sympathetic dystrophy) that we call chronic post‐ischemia pain (CPIP). The method involves placing a tourniquet (a tight fitting O‐ring) on one hindlimb of an anesthetized rat just proximal to the ankle joint for 3 h, and removing it to allow reperfusion prior to termination of the anesthesia. Rats exhibit hyperemia and edema/plasma extravasation of the ischemic hindpaw for a period of 2–4 h after reperfusion. Hyperalgesia to noxious mechanical stimulation (pin prick) and cold (acetone exposure), as well as mechanical allodynia to innocuous mechanical stimulation (von Frey hairs), are evident in the affected hindpaw as early as 8 h after reperfusion, and extend for at least 4 weeks in approximately 70% of the rats. The rats also exhibit spontaneous pain behaviors (hindpaw shaking, licking and favoring), and spread of hyperalgesia/allodynia to the uninjured contralateral hindpaw. Light‐microscopic examination of the tibial nerve taken from the region just proximal to the tourniquet reveals no signs of nerve damage. Consistent with the hypothesis that the generation of free radicals may be partly responsible for CRPS‐I and CPIP, two free radical scavengers, N‐acetyl‐l‐cysteine (NAC) and 4‐hydroxy‐2,2,6,6‐tetramethylpiperydine‐1‐oxyl (Tempol), were able to reduce signs of mechanical allodynia in this model.

Peripheral and central hyperexcitability: Differential signs and symptoms in persistent pain

This target article examines the clinical and experimental evidence for a role of peripheral and central hyperexcitability in persistent pain in four key areas: cutaneous hyperalgesia, referred pain, neuropathic pain, and postoperative pain. Each suggests that persistent pain depends not only on central sensitization, but also on inputs from damaged peripheral tissue. It is instructive to think of central sensitization as comprised of both an initial central sensitization and an ongoing central sensitization driven by inputs from peripheral sources. Each of these factors, initial sensitization, ongoing central sensitization, and inputs from peripheral sources, contributes to the net activity in dorsal horn neurons and thus influences the expression of persistent pain or hyperalgesia. Since each factor, peripheral inputs and central sensitization (initial or ongoing), can contribute to both the initiation and maintenance of persistent pain, therapies should target both peripheral and central sources of pathology.

The formalin test: a validation of the weighted-scores method of behavioural pain rating

&NA; The formalin test was developed using an ordinal scale of weighted scores to rate the intensity of pain‐related behaviours in animals. However, no studies have been carried out to establish the ordinal relationship of the behavioural categories used to generate the weighted pain intensity scores. The purpose of the present study was to evaluate the validity of the weighted‐scores technique by assessing the ordinality of the behavioural categories associated with the specific category weights. The amount of time spent in each of 4 behavioural categories was measured as a function of the concentration of the formalin solution injected into the hindpaw of rats, and as a function of the dose of systemic morphine given to rats injected with a concentrated (5.0%) solution of formalin. The ordinal nature of the category weights was supported when the data were subjected to a polychotomous logistic regression for fitting an ordinal model.

Evidence that pregabalin reduces neuropathic pain by inhibiting the spinal release of glutamate

J. Neurochem. (2010) 113, 552–561.

The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception

&NA; The present study examined the role of mGluRs in nociceptive responses of male Long‐Evans rats following a subcutaneous (s.c.) injection of 1% (30 &mgr;l) or 2.5% (50 &mgr;l) formalin to the plantar surface of the hindpaw. Intrathecal (i.t.) administration of the mGluR4/mGluR6‐mGluR8 agonist, l(+)‐2‐amino‐4‐phosphonobutyric acid (l‐AP4), the mGluR1/mGluR5 antagonists, (S)‐4‐carboxyphenylglycine ((S)‐4CPG) or (S)‐4‐carboxy‐3‐hydroxyphenylglycine ((S)‐4C3HPG), but not the non‐selective antagonist, (+)‐&agr;‐methyl‐4‐carboxyphenylglycine ((+)‐MCPG), to the lumbar spinal cord slightly reduced second phase nociceptive responses. An i.t. injection of the mGluR1/mGluR5 agonist, (RS)‐3,5‐dihydroxyphenylglycine ((RS)‐DHPG) or the mGluR2/mGluR3 agonist, (1 S,3 S)‐1‐aminocyclopentane‐1,3‐dicarboxylic acid ((1 S,3 S)‐ACPD), but not (2 S,1′ R,2′ R,3′ R)‐2‐(2′3′‐dicarboxy‐cyclopropyl)‐glycine (DCG‐IV), dose‐dependently enhanced formalin‐induced nociception in the second phase. In addition, the facilitation of nociceptive responses induced by (1 S,3 S)‐ACPD or (RS)‐DHPG was reduced by prior i.t. administration of the mGluR antagonists, (+)‐MCPG or (S)‐4C3HPG, respectively, as well as by the N‐Methyl‐ d‐aspartate (NMDA) receptor antagonist, d(−)‐2‐amino‐5‐phosphonopentanoic acid (d‐AP5). These results indicate that although mGluRs may play a minor role in formalin‐induced nociception, mGluR agonist‐related facilitation of formalin scores may reflect an interaction with the NMDA receptor.

Contribution of protein kinase C to central sensitization and persistent pain following tissue injury

This paper provides evidence that central sensitization and persistent nociception following formalin-induced tissue injury in rats is dependent on the production of protein kinase C. Persistent nociceptive behavior in rats induced by subcutaneous formalin injection was significantly reduced by intrathecal pretreatment with a phospholipase C inhibitor (neomycin), and an inhibitor of protein kinase C (W-7), and was significantly enhanced by a phorbol ester (phorbol 12-myristate 13-acetate, PMA) and a stimulator of protein kinase C (SC-10). It is expected that noxious inputs associated with tissue injury produce a release of aspartate and glutamate within the spinal dorsal horn which by acting at ionotropic (NMDA) and metabotropic excitatory amino acid receptors produce an increase in intracellular messengers such as calcium and diacylglycerol which stimulate protein kinase C.