Sensitization Of Dorsal Horn Neurons Research Articles

AMPA receptors at primary afferent synapses in substantia gelatinosa after sciatic nerve section.

Increased excitability of superficial laminae of the spinal cord may contribute to the pathological pain consequent to peripheral nerve injury. Among several mechanisms that may be responsible for this occurrence is upregulation of receptors for glutamate in the spinal cord. To explore this possibility, we investigated changes in AMPA receptors in substantia gelatinosa of rats after section of the sciatic nerve. Immunofluorescence was performed on sections from the fourth lumbar segment. Quantitative analysis of digitally captured images suggested that staining for an antibody to a sequence shared by GluR2 and GluR3 (GluR2/3) was increased on the side ipsilateral to the lesion. To determine whether antigen accumulation was at synaptic sites and to probe whether it was selective for primary afferent terminals, we performed electron microscopy on immunogold-labelled material. Gold particles coding for GluR2/3 subunits were counted from synaptic active zones of glomerular terminals in substantia gelatinosa that originate from small calibre afferent fibres, and from active zones of terminals of probable intrinsic origin. Counts were significantly increased on the side ipsilateral to the lesion only at synapses of primary afferent terminals. These results document selective upregulation of receptor protein at the synapse. This upregulation may contribute to the increased sensitivity of dorsal horn neurons following peripheral nerve injury.

Referred pain induced by injection of capsaicin into the rat gastric artery

Rationale: Referred pain (or secondary hyperalgesia) is an increased response to noxious stimuli distant from the site of injury. This secondary hyperalgesia is thought to reflect hyperactivity of central neurons, including those in the spinal dorsal horn. The hypothesis tested was that injury to the stomach will result in sensitization of dorsal horn neurons and cutaneous secondary hyperalgesia. Results: In Experiment 1, behavioral tests for mechanical (yon Frey filaments) and heat sensitivity of the abdomen were performed before and at varying times after gastric artery capsaicin injection. Assessment of spontaneous behaviors demonstrated that capsacin (0.1, 0.3 or 1.0%, 100~l) injected into the left gastric artery induced motor inhibition or arousal at the time of injection. However, capsaicin did not produce vocalization or other signs of distress. There was a dose-dependent decrease in mechanical thresholds on the abdomen 15 rain after capsaicin injection that remained decreased for 3h. No changes were observed in the mechanical threshold for the ipsilateral hindpaw or the latency to respond to radiant heat for the abdomen or paw. To evaluate for possible systemic distribution of capsaicin, the effects of capsaicin injection on plasma extravasation were examined using Evan's Blue dye. Plasma extravasation was confined to the corpus of the stomach; no dye was visible in the abdominal skin in the area of secondary hyperalgesia or other viscera. In Experiment 2, extracellular recordings were made from dorsal horn neurons sensitive to gastric distention before and after injection of capsaicin (0.1%, 100 ~l). At the time of injection, capsaicin evoked high frequency bursts of activity in neurons that lasted up to 5 min, demonstrating that neurons receive nociceptive information from gastric primary afferent fibers. Spinal neurons sensitive to gastric distension were sensitized by capsaicin. Specifically, there was an increase in background discharges of the cells and also an enhanced responsiveness of the cells to gastric distention (10-80 mmHg) 30 min and 60 rain after capsaicin injection. Conclusions: These results suggest that cutaneous secondary hyperalgesia to mechanical stimulation (but not heat) occurs in the stomach viscorotomes on the abdominal wall in response to gastric neurogenic inflammation. Additionally, dorsal horn neurons responsive to gastric stimulation become hyperactive following injection of capsaicin into the gastric artery, revealing central sensitization. The changes observed after injection of capsaicin into the gastric artery are similar to those observed following capsaicin injection into the skin. The convergence of somatic and visceral primary afferent fibers onto dorsal horn neurons is likely the basis of cutaneous hyperalgesia (i.e., referred pain) associated with gastritis. Supported by NS 19912.

Effects of intrathecally administered lamotrigine, a glutamate release inhibitor, on short- and long-term models of hyperalgesia in rats.

Lamotrigine is a sodium channel blocker that inhibits the neuronal release of glutamate. Systemic administration of lamotrigine induces analgesia in short- and long-term models of hyperalgesia in rats. Considering the key role of N-methyl-D-aspartate receptors in the sensitization of dorsal horn neurons that leads to hyperalgesia, the author hypothesizes that intrathecally injected lamotrigine would be effective in reducing the hyperalgesia. Short-term hyperalgesia was induced by unilateral intraplantar injection of prostaglandin E2. Long-term hyperalgesia was produced by treating rats with streptozotocin, which causes diabetic neuropathy and, in a different group of animals, by loose ligation of the sciatic nerve (chronic constriction injury). Hyperalgesia was assessed by measuring withdrawal reaction time after paw pressure, and analgesia was measured by the thermal tail-flick test. In the short-term model, intrathecally administered lamotrigine (12.5, 25.0, and 100.0 microg) produced a dose-dependent increase in the reaction time of the hyperalgesic paw. The highest dose that completely restored the reaction time to control levels (26-29 s) from the hyperalgesic levels (12-15 s) did not affect the reaction time of the normal contralateral paw. In the tail-flick test, a consistent effect could be observed only with doses of 200 microg, which caused transient motor impairment of the hind paws. In the long-term models of hyperalgesia, intrathecally administered lamotrigine produced a dose-dependent and long-lasting (24-48 h) antihyperalgesic effect. Intrathecally administered lamotrigine produced a spinal, dose-dependent, and long-lasting antihyperalgesic effect in short- and long-term neuropathic models of hyperalgesia.

Spinal R-phenyl-isopropyl adenosine inhibits spinal dorsal horn neurons responding to noxious heat stimulation in the absence and presence of sensitization

The effects of spinally administered R(−) N 6-(2-phenylisopropyl) adenosine (R-PIA) on spinal dorsal horn neurons were investigated in anesthetized rats. Extracellular, single-unit recordings were measured during noxious heating of receptive fields on the hind paw. Three series of experiments were carried out to characterize the effects of R-PIA on spinal dorsal horn neuronal activity. In the first set of experiments, R-PIA dose-dependently suppressed noxiously evoked activity of spinal dorsal horn neurons. In the second set of experiments, R-PIA suppressed noxiously evoked activity in neurons sensitized by the topical application of mustard oil to a region of skin adjacent to their receptive fields. In the third set of experiments, R-PIA prevented mustard oil induced sensitization of dorsal horn neurons. In all cases, the adenosine receptor antagonist theophylline reversed the action of R-PIA. The results of these investigations indicate the involvement of spinal adenosine receptors in spinal pathways of central sensitization and in the modulation of somatically induced noxious pain.

Chronic central pain after spinal cord injury.

Spinal cord injury (SCI) frequently results in dysesthesias that have remained refractory to clinical treatments despite a variety of interventions. The failure of therapeutic strategies to treat dysesthesias after SCI is due to the lack of attention given to mechanisms that elicit chronic pain following SCI. An overview of the literature with respect to the development of chronic pain in the SCI patient population will be given. In addition, a mammalian model of chronic central pain following spinal cord trauma will be presented. The model is characterized by the development of mechanical and thermal allodynia, as demonstrated by measuring the thresholds of accepted nociceptive tests, the paw withdrawal responses accompanied by changes in behavior consistent with the experience of noxious stimuli. In addition, vocalization responses that are accompanied by postural and behavioral changes consistent with the receipt of a noxious stimulus and involving supraspinal pathways are measured. Locomotor function was also tested and scored using the Basso, Beattie, and Bresnahan (BBB) open field test scale. Our data indicate that somatosensory thresholds for both mechanical and thermal stimuli that elicit paw withdrawal (flexor reflex) or vocalizations, accompanied by complex changes in behavior, are significantly different following SCI. These changes represent the development of mechanical and thermal allodynia. To determine the underlying mechanism for the altered sensory responses, we used electrophysiological techniques to determine if nociceptive dorsal horn neurons demonstrated increased excitability to peripheral stimulation as evidenced by increased responses to natural somatosensory stimuli. The data presented support the development of central sensitization of dorsal horn neurons after spinal cord hemisection. This provides a mechanism for the development of mechanical and thermal allodynia after SCI. Hypotheses that account for the development of the central pain state after SCI, as well as therapeutic interventions to ameliorate the pain state, are discussed.

Formalin-evoked Fos expression in spinal cord is enhanced in morphine-tolerant rats

It has been hypothesized that tolerance to the analgesic effects of morphine results from the development of a compensatory response in neurons that express the opioid receptor or in neural circuits in which those neurons participate. The compensatory response establishes a sensitized state in these neurons. To determine if administration of a noxious stimulus can unmask a sensitization of dorsal horn neurons in morphine-pelleted rats, we injected morphine-tolerant and control rats with formalin into the plantar surface of the hindpaw, counted the number of flinches for 2 h and then processed the lumbar cord for Fos immunocytochemistry. Although there was no significant difference in flinching behavior between the morphine-tolerant and control groups, we recorded significantly increased total Fos-like immunoreactivity at the L4/5 and L2 segments both ipsilateral and contralateral to the site of formalin injection in the morphine-tolerant rats compared to the control rats. These results suggest that lumbar spinal cord neurons are sensitized during the development of tolerance, that the sensitization can be unmasked by the administration of a noxious stimulus and that it is manifested as increased expression of the Fos protein in the lumbar cord.

Pain mechanisms involved in musculoskeletal disorders.

This manuscript is intended to give a basic review of the peripheral and spinal neuronal mechanisms involved in the processing of musculoskeletal pain. There is a complicated neuronal network in the periphery and the spinal cord for the processing of nociceptive information. Injury to a muscle (inflammation or ischemia) or a joint (inflammation) results in sensitization of peripheral nociceptors. There is then an increased transmission to and increased release of neurotransmitters in the dorsal horn of the spinal cord. Dorsal horn neurons sensitized by the peripheral injury demonstrate increased background activity, increased receptive field size, and increased responses to peripherally applied stimuli. The increased release of neurotransmitters and the sensitization of dorsal horn neurons is dependent on activation of N-methyl-D-aspartate (NMDA), non-NMDA excitatory amino acid, and neurokinin 1 receptors. Behavioral changes typical of inflammatory pain are observed in arthritic rats. These behavioral changes can be modified by a variety of drugs, including opioids, excitatory amino acid receptor antagonists, or neurokinin receptor antagonists. In addition to processing nociceptive information following joint or muscle injury, the spinal cord controls peripheral joint inflammation. Production of dorsal root reflexes, antidromic action potentials, would be expected to result in the release of inflammatory neuropeptides [substance P and calcitonin gene-related peptide (CGRP)] from the terminals of primary afferents at the site of injury. The release of substance P and CGRP would potentiate the inflammatory response in the periphery.

Peroneal afferent nerve discharges underlying the behavioral response to the formalin test.

Subcutaneous injection of formalin into the hindpaw of the rat results in a biphasic behavioral response consisting of flinching of the injected paw. It is postulated that the second-phase response is related to sensitization of spinal cord neurons rather than to resumption of peripheral nociceptor activity. On removal from anesthesia with 3% halothane, 10 rats were given a subcutaneous injection of formalin (5%, 50 microL) into the dorsum of the hindpaw. Behavioral response to the formalin test were observed for the subsequent hour. In five sodium pentobarbital-anesthetized rats, peroneal afferent nerve activity was recorded for 1 hour following similar subcutaneous injection of formalin. During standard formalin testing in unanesthetized rats, flinching peaked between 1 and 2 minutes following injection (phase 1 response), ceased between 5 and 10 minutes, and recommenced after 15 minutes with a second peak at 45 minutes (phase 2). In sodium pentobarbital-anesthetized rats, peroneal afferent nerve activity increased transiently during the time course of the phase 1 behavioral response but showed no subsequent increase in activity during the ensuing 55 minutes. The results are consistent with the hypothesis that the initial behavioral response to formalin injection is mediated by high peripheral nerve activity, while the second phase is mediated by sensitization of dorsal horn neurons in conjunction with low persistent levels of afferent activity.

Possible Role of Protein Kinase C in the Sensitization of Primate Spinothalamic Tract Neurons

The responsiveness of spinal cord nociceptive neurons to innocuous mechanical stimuli can be increased by the release of excitatory amino acids (EAAs) and peptides attributable to an injury-induced barrage of impulses. This sensitization of spinal dorsal horn neurons can also result from administration of phorbol ester by microdialysis, presumably by direct activation of protein kinase C (PKC). This study was designed to examine the effects of central sensitization of spinothalamic tract (STT) neurons produced by intradermal injection of capsaicin on the descending inhibition driven from the periaqueductal gray (PAG) and the possible role of PKC in this process in anesthetized monkeys. Sensitization of responses of STT cells to mechanical stimuli was induced by intradermal injection of capsaicin. PAG inhibition was significantly attenuated when sensitization of responses to mechanical stimuli occurred. However, perfusion of the spinal cord with NPC15437 (a selective PKC inhibitor) by microdialysis could prevent the sensitization of the responses to mechanical stimuli and the reduction in PAG inhibition of these responses induced by capsaicin injection. Results similar to those produced by capsaicin injection were observed when a PKC activator, phorbol ester (12-O-tetradecanoylphorbol-13-acetate), was infused within the dorsal horn by microdialysis. An inactive phorbol ester (4 alpha-phorbol 12,13-didecanoate) had no effect. These results provide evidence that the activation of PKC contributes to the development of central sensitization in dorsal horn neurons produced by chemical stimulation with capsaicin. Attenuation of the effectiveness of PAG inhibition takes place when the sensitization of dorsal horn cells develops, and PKC may play a significant role in this process.

NGF as a mediator of inflammatory pain

The chapter reviews some of recent evidence which suggests that one neurotrophin, nerve growth factor (NGF), is a peripherally produced mediator of some persistent pain states, notably those associated with inflammation. The evidence for this proposal is as follows. 1. The endogenous production of NGF regulates the sensitivity of nociceptive systems. Behavioural and electrophysiological studies have shown that sequestration of constitutively produced NGF leads to decrease nociceptor sensitivity. 2. In a wide variety of experimental inflammatory conditions NGF levels are rapidly increased in the inflamed tissue. 3. The high-affinity NGF receptor, trkA, is selectively expressed by nociceptive sensory neurons particularly those containing sensory neuropeptides such as substance P and CGRP. 4. The systematic or local application of exogenous NGF produces a rapid and prolonged behavioural hyperalgesia in both animals and humans. Exogenous NGF has also been found to activate and sensitize fine calibre sensory neurons. 5. In a number of animal models, much of the hyperalgesia associated with experimental inflammation is blocked by pharmacological "antagonism' of NGF. The mechanisms by which NGF up-regulation in inflamed tissues might lead to sensory abnormalities is also discussed. In particular, evidence is reviewed which suggests that increased NGF levels leads to both peripheral sensitization of nociceptors and central sensitization of dorsal horn neurons responding to noxious stimuli.

Muscarinic cholinergic hyperactivity and negative symptoms in schizophrenia

Sensitization of dorsal horn neurons (DHNs) in the spinal cord is dependent on pain-related synaptic plasticity and causes persistent pain. The DHN sensitization is mediated by a signal transduction pathway initiated by the activation of N-methyl-d-aspartate receptors (NMDA-Rs). Recent studies have shown that elevated levels of reactive oxygen species (ROS) and phosphorylation-dependent trafficking of GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPA-Rs) are a part of the signaling pathway for DHN sensitization. However, the relationship between ROS and AMPA-R phosphorylation and trafficking is not known. Thus, this study investigated the effects of ROS scavengers on the phosphorylation and cell-surface localization of GluA1 and GluA2. Intrathecal NMDA- and intradermal capsaicin-induced hyperalgesic mice were used for this study since both pain models share the NMDA-R activation-dependent DHN sensitization in the spinal cord. Our behavioral, biochemical, and immunohistochemical analyses demonstrated that: 1) NMDA-R activation in vivo increased the phosphorylation of AMPA-Rs at GluA1 (S818, S831, and S845) and GluA2 (S880) subunits; 2) NMDA-R activation in vivo increased cell-surface localization of GluA1 but decreased that of GluA2; and 3) reduction of ROS levels by ROS scavengers PBN (N-tert-butyl-α-phenylnitrone) or TEMPOL (4-hydroxy-2, 2, 6, 6-tetramethylpiperidin-1-oxyl) reversed these changes in AMPA-Rs, as well as pain-related behavior. Given that AMPA-R trafficking to the cell surface and synapse is regulated by NMDA-R activation-dependent phosphorylation of GluA1 and GluA2, our study suggests that the ROS-dependent changes in the phosphorylation and cell-surface localization of AMPA-Rs are necessary for DHN sensitization and thus, pain-related behavior. We further suggest that ROS reduction will ameliorate these molecular changes and pain.

Halothane enhances suppression of spinal sensitization by intrathecal morphine in the rat formalin test.

Injection of formalin in the hindpaw of the rat induces intense C-fiber activity accompanied by brief flinching of the injected paw (phase 1) and gives rise to facilitated spinal processing characterized by renewed flinching beginning 15 min after injury and lasting 40 min or more (phase 2). In previous work, isoflurane, administered during phase 1, slightly reduced phase-2 activity, whereas the addition of intrathecal morphine dramatically inhibited phase 2, even with naloxone reversal 6 min after the formalin injection. We used a similar model to determine whether intrathecal morphine could block spinal sensitization in the absence of inhalation anesthetic. Hot plate tests at 52 degrees C and radiant heat-evoked hindpaw withdrawal tests were used to determine optimal doses of agonists and antagonists. The formalin test was carried out on male Sprague-Dawley rats, which were divided into five groups. A combination of naloxone 0.5 mg/kg and naltrexone 0.5 mg/kg was administered subcutaneously 6 min after the formalin injection to all animals except controls (group 1) to prevent ongoing opioid effect. Groups 1-3 received intrathecal saline, and groups 4 and 5 received intrathecal morphine 30 micrograms 20 min before formalin injection. Halothane was administered for 1-2 min to facilitate formalin injection for groups 1, 2, and 4. In groups 3 and 5 halothane was administered from 5 min before to 6 min after formalin injection. The number of flinches per minute was counted 1 and 5 min after formalin administration and thereafter at 5-min intervals for 1 h. The total number of flinches at 1 and 5 min was considered as phase-1 activity, and the total number of flinches during the 10-60-min interval was considered as phase 2. Phase-2 activity for groups 1 and 2 was nearly identical, demonstrating no appreciable effect of the opioid antagonists alone. Groups 3 (halothane alone) and 4 (morphine alone) exhibited a significant decrease in phase-2 activity. Group 5 (morphine plus halothane) demonstrated a profound decrease in phase-2 activity, which was significantly more profound than that of groups 3 or 4. Intrathecal morphine, administered before formalin injection but antagonized before the onset of phase 2 of the formalin test, significantly suppresses sensitization of dorsal horn neurons. This suppression is significantly increased by coadministration of halothane anesthesia.

The role of substance P in rheumatic disease

Peptides produced within the nervous system play an important role in pain and mediation of inflammation. One of the most common neuropeptides is substance P (SP), which is released from the central and peripheral terminals of sensory nerves. SP is involved in pain transmission within the central nervous system, where it appears to modulate widespread and prolonged changes in the sensitivity of dorsal horn neurons to various stimuli. Peripheral release produces vasodilatation and plasma extravasation as well as a wide range of effects on the cellular components of the inflammatory cascade. Immunohistochemical studies show that all sections of joint tissue are well innervated with SP-containing sensory nerves. Joint inflammation results in increased production and transport of SP to both central and peripheral sites, including synovium. Support for a specific neurogenic influence on joint disease comes from clinical observations and from studies showing that the course of arthritis can be modified by manipulation of neurological pathways. Experimental joint disease can be exacerbated by intraarticular injections of SP, whereas depletion of SP stores using capsaicin inhibits the early articular response to inflammatory agents and improves the clinical features and outcome of chronic arthritis.

The effect of trans-ACPD, a metabotropic excitatory amino acid receptor agonist, on the responses of primate spinothalamic tract neurons

The responses of primate spinothalamic tract (STT) neurons to innocuous and noxious mechanical stimuli applied to the skin can be enhanced for more than an hour following prolonged noxious stimulation. This increased responsiveness is thought to reflect sensitization of dorsal horn neurons and may help account for secondary hyperalgesia and mechanical allodynia. The proposal that central sensitization is due to the activation of second messenger systems was tested in this study by examining the effect of trans-ACPD ( trans- d,l-1-amino-1, 3-cyclopentanedicarboxylic acid), an agonist of metabotropic excitatory amino acid (EAA) receptors, introduced into the dorsal horn by microdialysis. A low dose of trans-ACPD resulted in an increase in the responses of STT cells to an innocuous mechanical stimulus (BRUSH), but no increase in the responses to noxious mechanical and thermal stimuli or in the excitation produced by iontophoretically applied EAAs. A high dose of trans-ACPD caused a transient increase in background activity, but no change in the responsiveness of spinothalamic cells to any of the test stimuli. It is concluded that low doses of trans-ACPD can selectively enhance transmission through interneuronal pathways mediating tactile inputs to spinothalamic cells.

The effect of phorbol esters on the responses of primate spinothalamic neurons to mechanical and thermal stimuli

1. Sensitization of dorsal horn neurons is thought to play an important role in pain perception, secondary hyperalgesia, and allodynia. Recent experimental evidence suggests that the sensitization of dorsal horn neurons is induced by combined increased release of excitatory amino acids and peptides in the spinal cord dorsal horn from nociceptive primary afferents due to an injury-caused barrage of impulses. We tested the hypothesis that protein kinase C (PKC) is involved as a second messenger in this process of neuronal sensitization. To activate PKC, infusion of a phorbol ester [12-O-tetradecanoylphorbol-13-acetate (TPA)] into the dorsal horn through a microdialysis fiber was used. During TPA infusion the background activity of spinothalamic (STT) neurons increased substantially. After TPA application, while the background activity of the STT neurons was still increased, the responses evoked by either innocuous or noxious mechanical stimulation of the cutaneous receptive field did not change from the control level. However, 1 h after TPA administration the background activity returned to the control level and responses to innocuous mechanical stimuli were significantly elevated. The responses of STT cells to noxious heat and noxious mechanical stimuli did not change significantly after TPA administration. When a phorbol ester that does not activate PKC was applied (alpha-TPA), no significant changes in background or evoked activity of STT cells were observed. Our results provide evidence that PKC may play an important role in the process of sensitization of dorsal horn neurons to innocuous mechanical stimuli.

Does sensitization of responses to excitatory amino acids underlie the psychophysical reports of two modalities of increased sensitivity in zones of secondary hyperalgesia?

S ensitization, or enhancement of the responses of dorsal horn neurons to afferent stimuli, is emerging as one mechanism for the production of secondary hyperalgesia. The focus article by Dr. Wilcox does a wonderful job of highlighting the complexity of the chemical bases for sensitization of dorsal horn neurons. In general, sensitization of the responses of sensory neurons in the spinal cord appears to fall into two broad classes: that produced by loss of normal inhibitory processes, disinhibition,~5,2s; and that produced by an increase in the efficacy of excitatory pathways, facil i tation? ,3, 6-11,14.21,24 Both of these processes, which presumably result in an increase in the activity of projection neurons, potentially involve multiple mechanisms. We would like to raise a few additional points concerning enhancement of excitatory pathways in the dorsal horn after peripheral injury or inflammation. Dr. Wilcox reviews many studies in his focus article that show that sensitization of neurons in the dorsal horn appears to require the actions of excitatory amino acids, primarily glutamate, but also aspartate, and the neurokinin peptide, substance P (SP). The excitatory amino acids and the neuropeptides seem

Potentiated expression of FOS protein in the rat spinal cord following bilateral noxious cutaneous stimulation

A noxious mechanical or chemical stimulus to the ventral skin of one hindpaw induced the expression of FOS proteins ipsilaterally in the spinal dorsal horn neurons in the rat. The number of FOS-labelled cells reached a maximum at 2–3 h, and decayed to basal levels within 6 h after the stimulus. When a first noxious stimulus was applied to the contralateral hindpaw 1–1.5 h prior to this stimulus, the number of FOS-labelled cells increased, over all laminae, to 153% (mechanical) and 164% (chemical) compared to the number produced by a single stimulus. This effect of a prior stimulus in increasing the number of FOS-labelled cells produced by a contralateral stimulus persisted for several hours after the first stimulus. The results are interpreted as a sensitization of dorsal horn neurons induced by peripheral noxious stimuli, which is manifest at the molecular biological level.

Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey

Sensitization of the responses of dorsal horn neurons to mechanical stimulation may play a role in the generation of hyperalgesia. Intradermal injection of capsaicin (CAP) provides a model of experimental hyperalgesia that possesses a component of allodynia. This hyperalgesia is produced by chemical stimulation of C-fibers, leading to sensitization of dorsal horn neurons, including spinothalamic tract (STT) cells. The changes in the physiological responses of STT neurons following intradermal CAP in monkeys parallel the acute pain and hyperalgesia produced by intradermal CAP in humans. The present study addresses the role that excitatory amino acids (EAAs) may play in the sensitization of STT neurons by intradermal CAP. Our results show that the background discharge rate and the responses of STT cells to mechanical stimulation increase following intradermal CAP. In addition, the responses of the sensitized cells to one or more iontophoretically released EAA agonists, including NMDA, glutamate, aspartate, kainate, DL-alpha-amino-3-hydroxy-5-methyl-isoxazoleproprionic acid, and/or quisqualate, increase following intradermal CAP. It is proposed that an increase in the responses of STT neurons to EAAs contributes to the hyperalgesia produced by this noxious chemical stimulus.

Mechanisms of sympathetic pain

In some chronic pain states, notably causalgia and reflex sympathetic dystrophy, activity in sympathetic efferent neurones can exacerbate the pain and sympathectomies relieve it. These patients are said to have sympathetically maintained pain (SMP). In normal tissue, activity in postganglionic sympathetic efferents does not produce pain, nor is it capable of activating nociceptive sensory neurones. It can, however, induce modest firing in some mechanoreceptors. SMP is often held to result from a vicious circle of events which include changes in peripheral and central somatosensory processes, and most importantly a positive feedback element in the form of sympathetic efferent neurones which, by activating sensory neurones in the periphery, completes the vicious circle. Several specific hypotheses have been advanced as to the primary pathophysiological cause of pain in these patients. Suggestions, largely deriving from observations on animal models, include: ephaptic transmission, adrenergic receptors on sensory neurones, indirect coupling of sympathetic and sensory neurones, sensitization of nociceptive afferents, and, in the central nervous system, sensitization of dorsal horn neurones. All these suggestions have some supporting evidence, but none are able to adequately explain all the disturbances seen in patients with SMP.