Cutaneous Hyperalgesia Research Articles

Brain Mechanisms of Persistent Pain States

SUMMARYObjectives: The objective of this review is to explain the relationships between neural mechanisms of persistent pain and neural representations of these conditions in brains of animal models and in brains of human pain patients.Findings: Animal models of persistent pain, such as that which results from constrictive injury to the sciatic nerve or from intradermal injections of formalin, are accompanied by spatially widespread yet somatotopically organized increases in spinal cord dorsal horn neural activity and by similar widespread somatotopically organized increases in several pain-related areas of the brain. Consistent with these animal studies, human brain imaging studies that examine neural representations of visceral and cutaneous hyperalgesia have found that both forms of hyperalgesia are represented in many of the same multiple brain regions that are activated during acute normal pain, yet have a more extensive representation.Conclusions: Hyperalgesic states are represented by increased act...

Hypersensitivity to visceral and cutaneous pain in the irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal illnesses and is characterized by altered visceral perception. Previous studies in IBS have failed to demonstrate altered somatic or cutaneous perception. The aims of the study were to determine whether IBS patients have visceral hypersensitivity and cutaneous heat-induced hyperalgesia restricted to lumbosacral dermatomes, consistent with a localized segmental mechanism. Twelve patients (ten women, two men) with IBS and 17 control subjects (13 women, four men) rated pain intensity and unpleasantness to distension of the rectum (35, 55 mmHg) and thermal stimulation (45, 47°C) of the hand and foot. Patients with IBS demonstrated cutaneous allodynia/hyperalgesia to thermal pain applied to the hand and foot. The cutaneous hyperalgesia was pronounced in the lower extremity yet present in the upper extremity to a lesser extent. Psychological testing revealed the IBS patients report more state anxiety and a greater number of somatic symptoms that significantly correlated with most of the pain measures. However, they did not differ from controls on several personality trait measures. These results suggest that patients with IBS have visceral hyperalgesia and cutaneous hyperalgesia that is distributed over a considerable rostral-caudal distance yet optimally expressed in lumbosacral dermatomes. This distribution is consistent with patterns of spinal hyperexcitability observed in experimentally induced persistent pain conditions.

The effect of heat conditioning of the primary area before and after induction of hyperalgesia by topical/intradermal capsaicin or by controlled heat injury

The aim of the present study was to test the effect of heat conditioning before and after the induction of hyperalgesia. Three different methods were used for induction of hyperalgesia, topical capsaicin, intradermal capsaicin injection, and a controlled heat injury. The vascular (blood flow and skin temperature) and sensory changes (area of secondary hyperalgesia and ongoing pain) associated with the cutaneous hyperalgesia were compared. Each experiment consisted of two randomized sessions separated by at least 2 days. In one session, pre-conditioning of the skin by heat was performed 30 min before the induction of hyperalgesia using a probe at 45°C for 5 min in the center of the expected primary hyperalgesic area. After the induction of hyperalgesia, heat conditioning was performed twice in the center of the primary hyperalgesic area using a temperature of 2°C above the present individual pain threshold. On the contra-lateral arm, no heat conditioning was applied while hyperalgesia was induced using the same method. This session was evaluated as a control. The preconditioning induced an increased skin temperature in the primary area for both topical capsaicin and the controlled heat injury. Postconditioning caused increased blood flow in the secondary hyperalgesic area for the topical capsaicin method and increased blood flow in the primary hyperalgesic area for the controlled heat injury method. However, conditioning with heat in an attempt to increase the C-fiber input did not have any effect on the ongoing pain ratings and sensory test results in any of the methods. The results of the present study suggest that there is still a need for a better experimental model with more stable allodynia both between sessions and between subjects while at the same time minimizing discomfort to the volunteer.

Effect of Remifentanil on Pain and Secondary Hyperalgesia Associated with the Heat–Capsaicin Sensitization Model in Healthy Volunteers

The heat--capsaicin sensitization model was developed as a noninvasive and noninjurious human experimental pain model. The sequential application of moderate intensity thermal and topical chemical stimuli produces stable and long-lasting areas of cutaneous secondary hyperalgesia. The aim of the present study was to validate the heat--capsaicin sensitization model as a tool for testing analgesic drug efficacy. Responsivity of model-associated measures was tested with remifentanil, a potent and ultrashort acting mu-opioid agonist. Sensitization was induced by heating forearm skin with a thermode at 45 degrees C for 5 min, immediately followed by application of 0.075% capsaicin cream for 30 min. Sensitization was rekindled four times at 40-min intervals with the thermode at 40 degrees C for 5 min. After each rekindling, areas of secondary hyperalgesia were measured, and the painfulness of thermal stimulation in normal skin with 45 degrees C for 1 min (long thermal stimulation [LTS]) was rated. Before and during the second rekindling, remifentanil 0.10 microg x kg(-1) x min(-1) or saline-placebo was infused for 35 min. Infusion of remifentanil reduced the areas of secondary hyperalgesia to 29--30% of baseline size compared with 75--83% during placebo. Similarly, remifentanil reduced the painfulness of LTS to 29% of baseline severity compared with 84% during placebo. Areas of secondary hyperalgesia and LTS painfulness returned to baseline levels by the time of the third rekindling, demonstrating rapid disappearance of remifentanil analgesia and possibly transient spontaneous opioid withdrawal hyperalgesia. Using the heat-capsaicin sensitization model, opioid analgesia and suppression of secondary hyperalgesia was reliably demonstrated without skin injury.

Basic Science (33)

Perfusion of the mechanically compressed lumbar ganglion with lidocaine reduces mechanical hyperalgesia and allodynia in the rat. (University of Arkansas for Medical Sciences, Little Rock, AR) J Neurophysiol 2000;84:798–805.This study used an animal model of lumbar radiculopathy to investigate the neurological mechanisms of cutaneous hyperalgesia and tactile allodynia. The rat L5 dorsal root ganglion (DRG) was chronically compressed by inserting a hollow perforated rod into the intervertebral foramen. The DRG was constantly perfused through the hollow rod with either lidocaine or normal saline delivered by a subcutaneous osmotic pump. Behavioral evidence for neuropathic pain after DRG compression involved measuring the incidence of hindlimb withdrawals to both punctate indentations of the hind paw with mechanical probes exerting different bending forces and to light stroking of the hind paw with a cotton wisp. Behavioral results showed that for saline‐treated control rats: the withdrawal thresholds for the ipsilateral and contralateral paws to mechanical stimuli decreased significantly after surgery and the incidence of foot withdrawal to light stroking significantly increased on both ipsilateral and contralateral hind paws. Local perfusion of the compressed DRG with 2% lidocaine for 7 days at a low flow‐rate (1 μl/h), or for 1 day at a high flow‐rate (8 μl/h) partially reduced the decrease in the withdrawal thresholds on the ipsilateral foot, but did not affect the contralateral foot. The incidence of foot withdrawal in response to light stroking with a cotton wisp decreased significantly on the ipsilateral foot and was completely abolished on the contralateral foot in the lidocaine treatment groups. Conclude that compression of the L5 DRG induced central pain syndrome that included bilateral mechanical hyperalgesia and tactile allodynia. Results also suggest that a lidocaine block, or a reduction in abnormal activity from the compressed ganglia to the spinal cord, could partially reduce mechanical hyperalgesia and tactile allodynia. Comments by Marshall Devor, PhD.Tonic compression of the dorsal root ganglion (DRG) in animal preparations, and presumably also in man, causes sensory cells to become electrically hyperexcitable. The resulting spontaneous discharge is a cause of ongoing paresthesias and pain. Many believe that in addition, this ectopic activity can trigger and maintain central sensitization in the spinal cord, resulting in tactile hypersensitivity (allodynia and hyperalgesia) in the body parts innervated by the ganglion. This second effect of ectopic DRG activity, however, is controversial. Zhang and collaborators now provide strong new support for this idea by showing that lidocaine infusion into the DRG, with consequent block of the ectopic DRG firing, considerably reduces allodynia and hyperalgesia for the duration of the infusion (weeks). Here is a novel therapeutic approach that deserves a try.

Will ion-channel blockers be useful for management of nonneuropathic pain?

For neuropathic pain, there is evidence that the analgesic effect of intravenous sodium-channel blockers is robust and dose dependent. Oral agents are less impressive, but efficacious nonetheless, especially at higher doses. Despite the evidence from animal studies for a role of sodium channels in inflammatory hyperalgesia, the clinical evidence of analgesic effect of oral and intravenous sodium channel blockers in both acute and chronic nonneuropathic pain is equivocal. The results to date from human experimental pain models suggest a lack of effect of systemic lidocaine on acute nociceptive pain and that the effect on cutaneous hyperalgesia is modest, at best. Furthermore, the literature suggests that the systemic lidocaine analgesia is both dose and diagnosis dependent.

Enhanced excitability of sensory neurons in rats with cutaneous hyperalgesia produced by chronic compression of the dorsal root ganglion.

Pain and hyperalgesia can occur when the dorsal root ganglion (DRG) and its roots are deformed mechanically in association with injuries or diseases of the spine. To evaluate the electrophysiological changes that contribute to this sensory pathology, intracellular recordings were obtained in vitro from DRGs that had received a chronic mechanical compression [chronic compression of DRG (CCD)]. The compression was produced by inserting L-shaped rods ipsilaterally into the intervertebral foramina, one at L(4) and the other at L(5) in rats 1-14 days before the recording. Control rats received a sham operation. Postoperatively, the threshold force applied by punctate stimulation of the plantar surface of the hind paw decreased significantly on the foot ipsilateral to the CCD (mechanical hyperalgesia) but changed little on the contralateral foot or on either foot for control rats. DRG somata were viewed through a microscope during recording and classified as small, medium, and large according to their diameters. CCD cells in each size category were more excitable than those of comparable size from control rats as judged by the significantly lowered threshold currents and action potential voltage thresholds. Spontaneous activity was recorded in 11% of all the CCD cells tested. The spontaneous activity and/or changes in both the threshold currents and action potential thresholds were observed as early as one day after injury. The association of cutaneous hyperalgesia with changes in the electrophysiological properties of DRG cells suggests a possible role for intrinsic alterations in the membrane properties of compressed DRG cells in the production and persistence of chronic pain after certain spinal injuries or pathologies of the spine.

Experimental human muscle pain induced by intramuscular injections of bradykinin, serotonin, and substance P

After intramuscular (m. tibialis anterior) injection of three different algogenic substances, the pain intensity was continuously scored on a visual analogue scale (VAS) in eight volunteers. The subject drew the distribution of the local and referred pain areas on a map. Four times within the first hour after injection, the pressure pain–thresholds (PPTs) and supra pressure–pain thresholds were assessed at the injection point, 2 cm distal from the injection site, at the arm, and at the contralateral leg. Measurements were done before and after injection of 0.5 ml of the algogenic substance [bradykinin (BKN), serotonin (5-HT), substance P (SP)], and isotonic saline as control. Cutaneous sensitivity to mechanical stimuli was assessed with a Von Frey hair at the same location as PPT determinations.The pain intensity (VAS-peak) after BKN (2, 4, and 10 nmol) and 5-HT (2, 4, and 20 nmol) was significantly higher (p< 0.05) than after SP (0.2, 0.4, and 0.8 nmol) and isotonic saline. The VAS-peak after infusions of hypertonic saline was significantly higher (p< 0.05) compared with VAS-peaks after all other substances. A significantly larger (p< 0.05) local pain area was found after BKN compared with isotonic saline. After injections of hypertonic saline, the offsets of evoked pain were significantly longer (p< 0.05) and the local and referred pain areas were significantly larger (p< 0.05) compared with all other substances. There was no dose–response relation between the pain intensity and the different doses of BKN, 5-HT, and SP. PPTs and skin sensitivity were not affected by any of the injections.We conclude that under the present experimental conditions, BKN and 5-HT can produce low levels of muscle pain after intramuscular injection. In the used concentrations, however, BKN, 5-HT, and SP did not generate cutaneous or muscular hyperalgesia.

Epinephrine Produces a β-Adrenergic Receptor-Mediated Mechanical Hyperalgesia and In Vitro Sensitization of Rat Nociceptors

Hyperalgesic and nociceptor sensitizing effects mediated by the beta-adrenergic receptor were evaluated in the rat. Intradermal injection of epinephrine, the major endogenous ligand for the beta-adrenergic receptor, into the dorsum of the hindpaw of the rat produced a dose-dependent mechanical hyperalgesia, quantified by the Randall-Selitto paw-withdrawal test. Epinephrine-induced hyperalgesia was attenuated significantly by intradermal pretreatment with propranolol, a beta-adrenergic receptor antagonist, but not by phentolamine, an alpha-adrenergic receptor antagonist. Epinephrine-induced hyperalgesia developed rapidly; it was statistically significant by 2 min after injection, reached a maximum effect within 5 min, and lasted 2 h. Injection of a more beta-adrenergic receptor-selective agonist, isoproterenol, also produced dose-dependent hyperalgesia, which was attenuated by propranolol but not phentolamine. Epinephrine-induced hyperalgesia was not affected by indomethacin, an inhibitor of cyclo-oxygenase, or by surgical sympathectomy. It was attenuated significantly by inhibitors of the adenosine 3',5'-cyclic monophosphate signaling pathway (the adenylyl cyclase inhibitor, SQ 22536, and the protein kinase A inhibitors, Rp-adenosine 3',5'-cyclic monophosphate and WIPTIDE), inhibitors of the protein kinase C signaling pathway (chelerythrine and bisindolylmaleimide) and a mu-opioid receptor agonist DAMGO ([D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin). Consistent with the hypothesis that epinephrine produces hyperalgesia by a direct action on primary afferent nociceptors, it was found to sensitize small-diameter dorsal root ganglion neurons in culture, i. e., to produce an increase in number of spikes and a decrease in latency to firing during a ramped depolarizing stimulus. These effects were blocked by propranolol. Furthermore epinephrine, like several other direct-acting hyperalgesic agents, caused a potentiation of tetrodotoxin-resistant sodium current, an effect that was abolished by Rp-adenosine 3',5'-cyclic monophosphate and significantly attenuated by bisindolylmaleimide. Isoproterenol also potentiated tetrodotoxin-resistant sodium current. In conclusion, epinephrine produces cutaneous mechanical hyperalgesia and sensitizes cultured dorsal root ganglion neurons in the absence of nerve injury via an action at a beta-adrenergic receptor. These effects of epinephrine are mediated by both the protein kinase A and protein kinase C second-messenger pathways.

Attenuation of experimental pruritus and mechanically evoked dysesthesiae in an area of cutaneous allodynia

We investigated the effects of tactile allodynia on the itch and mechanically evoked dysesthesiae produced by an intradermal injection of histamine in human volunteers. After an intradermal injection of capsaicin into the volar surface of one forearm, there developed an area of tactile allodynia to stroking and hyperalgesia to pricking the skin. Histamine was then injected simultaneously into the area of allodynia (experimental arm) and into the opposite forearm (control arm). Magnitude estimates of itch were obtained every 15 s for 5 min, and the areas of cutaneous hyperalgesia (pricking-evoked pain), alloknesis (stroking-evoked itch), hyperknesis (pricking-evoked itch) and wheal and flare were measured. The areas of wheal and flare were not significantly different on the two arms. The magnitude of itch and the areas of hyperknesis and alloknesis developed normally on the control arm but were absent or greatly reduced on the experimental arm. Thus, both the itch and the alloknesis and hyperknesis normally induced by histamine were absent or greatly reduced when histamine was injected in an area of capsaicin-induced allodynia. These results are compatible with the hypothesis that activity in capsaicin-sensitive, nociceptive primary afferent neurons evokes a central neuronal inhibitory process that prevents or reduces the itch and mechanically evoked dysesthesiae normally produced by an intradermal injection of histamine.

Dextromethorphan and pain after total abdominal hysterectomy

Dextromethorphan is an N-methyl-D-aspartate (NMDA) receptor antagonist which has been shown to inhibit the development of cutaneous secondary hyperalgesia after tissue trauma. We studied 60 ASA I-II patients undergoing total abdominal hysterectomy in a randomized, double-blind, placebo-controlled study. Patients received either dextromethorphan 27 mg capsules, two doses before operation and three doses in the first 24 h after operation, or placebo. Visual analogue pain scores (VAS) at 24 and 48 h were assessed at rest, on coughing and on sitting up, and were not significantly different between groups. Morphine consumption from a patient-controlled analgesia (PCA) device was also not significantly different between groups. Evidence of secondary hyperalgesia was assessed with von Frey hairs 10 cm above the Pfannenstiel incision. Both groups of patients exhibited evidence of secondary hyperalgesia after 24 and 48 h but there were no significant differences between groups. There was also no difference between groups in VAS scores at 1 month.

Pathophysiology and diagnosis in patients with sympathetically dependent pain

Chronic pain in a distal extremity that is accompanied by autonomic dysfunction in the same region is taken to indicate reflex sympathetic dystrophy. Typically, hyperalgesia to light touch is present in addition to the spontaneous pain. The absence of heat hyperalgesia indicates that the underlying mechanism is central rather than peripheral sensitization. This mechanism is similar to that of secondary hyperalgesia in the intact skin surrounding an injury site. Sympathetically maintained pain (SMP) is diagnosed, when these sensory symptoms are reversible under sympathetic blockade. SMP is not due to hyperactivity of sympathetic efferents but to receptor supersensitivity, probably by overexpression of alpha(1)-adrenergic receptors on nociceptive primary afferents. This way normal levels of norepinephrine can cause pathological spontaneous activity of nociceptors which maintains the central sensitization. Chronic burning pain and cutaneous hyperalgesia may also be independent of the sympathetic innervation of the skin. In this case, central sensitization is maintained by other mechanisms. A role of the sympathetic nervous system in the pathogenesis of pain cannot be deduced simply from the simultaneous presence of sensory and autonomic clinical signs and symptoms. Therefore, sympathetic blockade in a patient initially is a diagnostic procedure, aiming to demonstrate the presence of the symptom SMP. Therapeutic blockade is only indicated after this demonstration. For the substantial number of patients with sympathetically independent pain, other treatment modalities are needed which may for example attack central sensitization.

Transient inhibition of responses to thermal stimuli of spinal sensory tract neurons in monkeys during sensitization by intradermal capsaicin

A secondary zone of cutaneous hyperalgesia in humans is characterized by increased pain to mechanical stimuli. In contrast, the perception of heat stimuli delivered to a secondary zone of hyperalgesia in humans often shows a paradoxical decrease in magnitude. A number of studies have shown that the responses of spinal cord neurons to cutaneous mechanical stimuli after peripheral injury model well the mechanical hyperalgesia. However, the responses of dorsal horn neurons to thermal stimuli after peripheral injury have not been as carefully studied. The present study examined the effects of intradermal capsaicin on the responses of spinal sensory projection neurons to cutaneous mechanical and thermal stimuli. Our observations indicate that the responses of identified sensory projection neurons to heat are transiently reduced at the same time that responses of these cells to mechanical stimuli are increased. These results confirm a role for sensory projection cells in signaling the sensory discriminative aspects of pain in humans and underscore the emerging complexity of dorsal horn circuitry and sensory processing.

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.

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.

Role of capsaicin-sensitive afferent nerves in initiation and maintenance of pathological pain

This commentary provides experimental data in support of the critical role of capsaicin-sensitive primary afferent fibers in the initiation and maintenance of pathological pain. The demonstration of capsaicin-induced, centrally-evoked cutaneous hyperalgesia, and of neuroplastic changes elicited by the degeneration of C-fiber primary afferent terminals following peripheral nerve damage, indicates a significant contribution of capsaicin-sensitive sensory ganglion neurons in the development of pathological pain conditions. [coderre &amp; katz]

An in vitro study of ectopic discharge generation and adrenergic sensitivity in the intact, nerve-injured rat dorsal root ganglion

A chronic, loose constriction of the sciatic nerve in rat produces behavioral signs of spontaneous pain and cutaneous hyperalgesia (Bennett and Xie, Pain, 33 (1988) 87–107) as well as an abnormal spontaneous activity and adrenergic sensitivity of certain dorsal root ganglion (DRG) cells with axons in the injured nerve (Kajander et al., Neurosci. Lett., 138 (1992) 225–228; Xie et al., J. Neurophysiol., 73 (1995)1811–1820) The present study investigated whether the spontaneous activity and adrenergic sensitivity were intrinsic properties of injured DRG cells and manifested in vitro, i.e., not dependent on intact blood circulation and an intact, functioning sympathetic nervous system. Two weeks after a loose constriction of the sciatic nerve, the L4 or L5 DRG with its ligated nerve and dorsal root attached was removed from the rat and placed in a chamber. Extracellular recordings were made from teased dorsal root fibers. Spontaneous activity (>0.05 imp/s in 3 min) originating within or close to the DRG was often found in C-, A δ- and A β-fibers from nerve-injured rats, but was rare in fibers with peripheral axons from uninjured nerve. The incidence of various patterns of spontaneous discharge was similar to that previously recorded in vivo. Nineteen of 30 C-fibers, four of five A δ- and three of seven A β-fibers from injured nerve responded to different doses of norepinephrine (NE) applied topically to the DRG. Five of seven C- and one of two A β-fibers from injured nerve responded to clonidine, a more selective α 2 adrenergic agonist. The thresholds ranged from 500 to 10 μM, the lowest dose delivered. None of the fibers from uninjured nerve responded to NE or clonidine (500 μM). Since the experiments were carried out in vitro in the intact DRG, the existence of spontaneous activity in DRG cells in nerve-injured rats was independent of any blood borne chemicals, such as norepinephrine. We hypothesize that abnormal activity and adrenergic sensitivity in injured DRG neurons are due to an intrinsic alteration of the cell body membrane.

Peripheral Modulatory Effects of Catecholamines in Inflammatory and Neuropathic Pain

Publisher Summary Basic science and clinical studies indicate that the sympathetic nervous system (SNS) may play a role in pathological states associated with pain and hyperalgesia, such as inflammation and neuropathic pain. Recent psychophysical studies provide pharmacological evidence that noradrenaline may influence pain sensation in normal human subjects. Studies indicate that norepinephrine (NE) produces hyperalgesia to heat stimuli when administered into the skin of normal subjects. The earlier animal studies utilized a mechanical search stimulus to identify nociceptors. More recent studies have recognized the presence of “silent” nociceptors in skin that are mechanically insensitive. In a recent psychophysical study, the effects of NE on cutaneous hyperalgesia in humans are investigated, using topical application of capsaicin as a model to induce hyperalgesia. Capsaicin is known to sensitize C-fibers to heat and lower the pain threshold to mechanical stimuli. The decrease in heat pain threshold (hyperalgesia) following capsaicin administration is prolonged at the site where NE is iontophoresed but not at the saline site, suggesting that NE increased heat hyperalgesia in skin treated with topical capsaicin. These effects of NE in humans are consistent with the neurophysiological observations in animals that NE and sympathoneural stimulation increase nociceptor discharges in inflamed skin.

Alpha 1-adrenoceptors in normal and hyperalgesic human skin.

1. Evidence of an adrenergic component of cutaneous hyperalgesia has recently been obtained in animal models of painful peripheral neuropathy. These findings have prompted speculation that an increased density or sensitivity of peripheral alpha-adrenoceptors contributes to sensory abnormalities and chronic neuropathic pain in conditions such as reflex sympathetic dystrophy. However, it is not known whether alpha-adrenoceptors are present at the site of nociception, either in hyperalgesic or normal skin. 2. We used the selective radioligand 125I-hydroxyphenyl-ethyl-aminomethyl-tetralone (HEAT) to label alpha 1-adrenoceptors, and quantitative autoradiography to assess the relative density of these receptors in skin samples from seven normal individuals and from the hyperalgesic and pain-free limbs of five patients with reflex sympathetic dystrophy. The distribution of autoradiographic grains over the epidermis and dermis was investigated in 10 microns serial transverse sections. 3. alpha 1-Adrenoceptors were identified in the epidermis and dermal papillae of normal individuals, and in the hyperalgesic and pain-free skin of patients with reflex sympathetic dystrophy. The density of alpha 1-adrenoceptors was greater in the epidermis and dermal papillae than further down in the dermis. 4. The mean density of alpha 1-adrenoceptors was significantly greater in the hyperalgesic skin of patients than in the skin of normal individuals (35.4 grains/1000 microns2 compared with 15.5 grains/ 1000 microns2, P < 0.01). The mean density of alpha 1-adrenoceptors in the pain-free skin of patients (26.9 grains/1000 microns2) fell midway between receptor density in hyperalgesic skin and in the skin of normal individuals, and did not differ significantly from either. 5. Our findings indicate that alpha 1-adrenoceptors are present in the epidermis, and suggest that their numbers may be increased in the hyperalgesic skin of patients with reflex sympathetic dystrophy. Further studies need to identify the dermal and epidermal cell types that express high densities of alpha 1-adrenoceptors, and to investigate their normal function and role in neuropathic pain.

The effect of Ketamine on stimulation of primary and secondary hyperalgesic areas induced by capsaicin -- a double-blind, placebo-controlled, human experimental study

The non-competitive NMDA-antagonist, Ketamine, was infused (i.v.) in healthy volunteers to study the effect on central excitability with the presence of cutaneous hyperalgesia. Hyperalgesia was established experimentally on the dorsum of the foot by topical application of capsaicin (1%). Different thermal and mechanical conditioning stimuli were applied to the primary and secondary hyperalgesic areas to modulate the central nociceptive excitability monitored by the nociceptive reflex. When the elicited reflex was combined with an activation of the secondary hyperalgesic area by continuous, non-painful, electrical stimulation, a facilitation of the reflex was observed. This indicates that summation of activity in non-nociceptive and nociceptive afferents can occur under mild pathological conditions. Conditioning thermal stimuli of the primary hyperalgesic area were employed to intensify the allodynia prior to testing this interaction between tactile and nociceptive activity. The same reflex facilitation was inhibited by Ketamine. Furthermore, Ketamine decreased the pain intensity associated with the stimuli eliciting the reflex. Psychophysical measures to single and repeated electrical and thermal (laser) stimuli applied within the hyperalgesic areas were also obtained. The intensity of pain sensations produced by single, painful, electrical stimuli applied to the primary hyperalgesic region was reduced after Ketamine infusion. Finally, five repeated, electrical stimuli applied to the secondary hyperalgesic area were used to assess the temporal summation threshold. Ketamine caused an increase in the summation threshold compared to the placebo treatment. In conclusion, these results demonstrate that (1) summation of activity in non-nociceptive and nociceptive afferents occurs under hyperalgesic conditions and, (2) this summation can be inhibited by NMDA-antagonists. Therefore, the study shows an apparent involvement of NMDA-receptors in some of the central mechanisms underlying secondary hyperalgesia.