Myelinated nociceptive afferents account for the hyperalgesia that follows a burn to the hand.

Monkeys and human subjects were exposed to a series of thermal stimuli before and after a 53 degrees C, 30-second burn to the glabrous skin of the hand. The responses of C- and A-fiber nociceptive afferents in the monkeys and subjective responses by the humans were compared. The burn resulted in increased sensitivity of the A fibers, decreased sensitivity of the C fibers, and increased pain sensibility (hyperalgesia) in the human subjects.

Coupling of action potential activity between unmyelinated fibers in the peripheral nerve of monkey.

Bidirectional coupling of action potential activity occurs between unmyelinated fibers in the normal peripheral nerve of monkey. The site of coupling is near the cutaneous nociceptive receptor associated with one of the fibers. This coupling could be due to an electrical synapse and could provide the basis for the flare associated with the axon reflex.

Peripheral and central mechanisms of cutaneous hyperalgesia.

Hyperalgesia after cutaneous injury can be divided into two phenomena: Primary hyperalgesia occurs at the site of injury and is characterized by hyperalgesia to mechanical and heat stimuli. Secondary hyperalgesia occurs outside the injury site and is characterized by mechanical hyperalgesia only. Hyperalgesia in inflammatory processes corresponds to primary hyperalgesia. Hyperalgesia in referred pain and neuropathic pain resembles secondary hyperalgesia (Table 3). Evidence for the latter would be strengthened if hyperalgesia to cooling stimuli, which is observed in neuropathic pain, was also demonstrated in referred pain and in secondary hyperalgesia. Some of the more likely neural mechanisms to explain primary and secondary hyperalgesia are illustrated in Fig. 8. Primary hyperalgesia to heat stimuli has a counterpart in the sensitization of peripheral nociceptors to heat stimuli (Fig. 8A), leading to similar changes in central neurons. In addition, the enlargement of the mechanical receptive field of primary afferent nociceptors to include the site of injury may account for the primary hyperalgesia to mechanical stimuli (Fig. 8B). In the literature, there are some contradictions with respect to the stimulus modalities to which hyperalgesia and sensitization occur. In spite of the well-documented sensitization of primary afferent nociceptors to heat stimuli, there are few studies on its molecular mechanisms. On the other hand, there is pharmacological evidence for a peripheral mechanism of primary mechanical hyperalgesia, but little direct evidence that nociceptors can be sensitized to mechanical stimuli by injury. This contradiction should spawn further investigations into the mechanical response properties of nociceptors and into the molecular mechanisms of heat sensitization. Secondary hyperalgesia to mechanical stimuli is likely due to the sensitization of central pain signalling neurons (CPSNs). This sensitization could involve only input from nociceptors (Fig. 8C), since mechanical pain thresholds after a cutaneous injury are of the same order as those of nociceptors. Central sensitization could also be the result of enhanced connectivity between low-threshold mechanoreceptors and CPSNs (Fig. 8D). This form of sensitization may account for the pain to light touch associated with neuropathic pain. Receptive field plasticity is a prevalent property of dorsal horn neurons and probably plays a vital role with regard to hyperalgesia. The molecular mechanisms of synaptic plasticity are currently subject to intense experimental investigation and may provide new insights on the mechanisms of pain and hyperalgesia.

Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors.

The recently cloned vanilloid receptor (VR1) is postulated to account for heat and capsaicin sensitivity in unmyelinated afferents. We sought to determine whether heat and capsaicin sensitivity also coexist in myelinated nociceptive afferents. Action potential (AP) activity was recorded from single A-fiber nociceptors that innervated the hairy skin in monkey. Before intradermal injection of capsaicin (10 microg/10 microl) into the receptive field, nociceptors were classified as heat-sensitive (threshold,

Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers.

Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.

Pain and hyperalgesia after intradermal injection of bradykinin in humans.

Pain and hyperalgesia, the perceptual campanions of tissue injury and inflammation, are thought to be in part attributable to the sensitization of primary afferent nociceptors by endogenously released chemicals, such as bradykinin. Bradykinin (0.1 to 10 nmol in 10 microliters) evoked a dose-dependent pain, hyperalgesia to heat stimuli, and wheal and flare when injected in a double-blind manner into the volar forearm intradermally. Though hyperalgesia to mechanical stimuli is a conspicuous feature of inflammatory pain, none was measurable for any of the bradykinin doses in response to graded nylon monofilament probes. A second injection of bradykinin (5- or 30-minute intervals) at the same site produced markedly less pain and hyperalgesia to heat stimuli, indicating that the algesic and hyperalgesic effects of bradykinin undergo tachyphylaxis. These findings suggest that bradykinin alone cannot account for all aspects of the hyperalgesia that occurs after inflammation.

Secondary hyperalgesia to mechanical but not heat stimuli following a capsaicin injection in hairy skin.

A psychophysical investigation was carried out to examine whether heat hyperalgesia exists within the secondary mechanical hyperalgesia zone surrounding a capsaicin injection site on hairy skin. A non-contact laser stimulator was used to deliver temperature controlled stimuli to sites within and outside the zone of mechanical hyperalgesia. Heat testing was carried out before and after the intradermal injection of 50 micrograms of capsaicin into the volar forearm. The zones of mechanical hyperalgesia to punctate and stroking stimuli and the region of flare were also mapped after the capsaicin injection. Heat pain thresholds inside the secondary mechanical hyperalgesic zone were not significantly different from thresholds outside the secondary mechanical hyperalgesia zone. In addition, pain ratings to an ascending series of heat stimuli delivered inside the zone of secondary hyperalgesia were not significantly different from pain ratings outside the zone of secondary hyperalgesia. Thus, there was no evidence for heat hyperalgesia within the zone of secondary hyperalgesia to punctate mechanical stimuli. Though the areas of punctate and stroking hyperalgesia were correlated, no correlation existed between the magnitude of capsaicin evoked pain and the areas mechanical hyperalgesia to punctuate and stroking stimuli or the area of flare. This suggests that independent mechanisms may mediate evoked pain, central sensitization that leads to mechanical hyperalgesia, and axon reflexive flare.

Effects of baseline skin temperature on pain ratings to suprathreshold temperature-controlled stimuli.

Variations in baseline skin temperature can be encountered in experimental and clinical pain states. Such variations have been shown to greatly alter the response to radiant heat stimuli when the temperature of the stimulus is not controlled. We carried out a psychophysical investigation to examine the influence of baseline skin temperature on pain ratings to temperature-controlled heat stimuli. A CO(2) laser thermal stimulator was used to deliver heat stimuli under radiometer feedback temperature control to the volar forearm. Each stimulus consisted of a 30 s controlled baseline interval (at 34 or 38 degrees C) followed by a stepped increase in temperature (to 46 or 47 degrees C for 1, 2 or 4 s). A run comprised one presentation of each of these12 different stimuli to different locations. Each experiment contained three runs. In runs 2 and 3, the stimulus intensity and duration at a given location were not changed, but the baseline temperature was alternated between 34 degrees C and 38 degrees C. The intensity of pain was rated using the technique of magnitude estimation. Mean normalized pain ratings for suprathreshold stimuli applied from the higher base temperature (1.03+/-0.03) were slightly greater than from the lower base temperature (0.96+/-0.03). In contrast, pain ratings to the 47 degrees C stimuli (1.11+/-0.03) were substantially greater than to the 46 degrees C stimuli (0.88+/-0.03). Thus a 4 degrees C change in baseline temperature has a smaller affect (about 8%) on pain ratings than a 1 degrees C change in stimulus temperature (about 27%). This suggests that variations in baseline skin temperature encountered in experimental and clinical pain states have only a minor impact on pain sensitivity to suprathreshold temperature-controlled stimuli.

A psychophysical study of secondary hyperalgesia: evidence for increased pain to input from nociceptors.

Substantial evidence suggests that the hyperalgesia to mechanical stimuli that occurs in an area of uninjured skin surrounding a site of injury (area of secondary hyperalgesia) arises from activity in low-threshold mechanoreceptors (LTMs). In this study, we have investigated if activity in mechanically sensitive nociceptors also contributes to this secondary hyperalgesia. It is known that all woollen fabrics excite LTMs, but that only the prickly ones activate mechanically sensitive nociceptors. Therefore, we have conducted a psychophysical study using a range of prickly and non-prickly woollen fabrics applied to normal and hyperalgesic skin to assess the roles of LTMs and nociceptors in secondary hyperalgesia. We have studied in 10 normal volunteers the sensations of fabric-evoked prickle and pain in normal and hyperalgesic skin. Secondary hyperalgesia was produced by intradermal injection of capsaicin (25 micrograms) into the volar skin of the forearm. Five woollen fabrics (2 non-prickly, 2 prickly and 1 intermediate) were presented, in a blind manner, to the skin before and after the capsaicin injection. The sensation of fabric-evoked prickle was not changed in hyperalgesic skin. On the other hand, little if any pain was evoked by the fabrics when applied to normal skin, but substantial pain was produced by all fabrics when applied to hyperalgesic skin. The pain ratings were graded with the ratings of prickle so that fabrics that evoked the greatest prickle also evoked significantly more pain. The magnitude of pain increased linearly with prickle sensation; the slope of this regression function increased substantially in hyperalgesic skin.(ABSTRACT TRUNCATED AT 250 WORDS)

Secondary hyperalgesia persists in capsaicin desensitized skin.

Several lines of evidence suggest that secondary hyperalgesia to punctate mechanical stimuli arises from central sensitization to the input from primary afferent nociceptors. Conventional C-fiber nociceptors respond to heat stimuli and yet heat hyperalgesia is absent in the region of secondary hyperalgesia. This evidence suggests that the central sensitization to nociceptor input does not involve heat sensitive nociceptors. To test this hypothesis, we investigated whether desensitization of heat sensitive nociceptors by topical application of capsaicin led to an alteration in the secondary hyperalgesia. Two 2x2 cm areas on the volar forearm, separated by 1 cm, were treated in 10 healthy volunteers. One of the areas was desensitized by treatment with 10% topical capsaicin (6 h/day for 2 days). The other site served as vehicle control. Hyperalgesia was produced 2 days later by an intradermal injection of capsaicin (50 microg, 10 microl) at a point midway between the two treatment areas. Secondary hyperalgesia to noxious mechanical stimuli was investigated by using a blade probe (32 and 64 g) attached to a computer-controlled mechanical stimulator. In the area of topical capsaicin treatment, there was a marked increase in heat pain threshold and decrease in heat pain ratings indicating a pronounced desensitization of heat sensitive nociceptors. However, touch threshold and pain to pinching stimuli were not significantly altered. The intradermal capsaicin injection led to the development of a similar degree of secondary hyperalgesia at both the vehicle and capsaicin treatment areas. These results indicate that capsaicin insensitive nociceptive afferents play a dominant role not only in normal mechanical pain but also in secondary hyperalgesia to noxious mechanical stimuli.

Pain activation of human supraspinal opioid pathways as demonstrated by [11C]-carfentanil and positron emission tomography (PET).

The role of the supraspinal endogenous opioid system in pain processing has been investigated in this study using positron emission tomography imaging of [11C]-carfentanil, a synthetic, highly specific mu opioid receptor (mu-OR) agonist. Eight healthy volunteers were studied during a baseline imaging session and during a session in which subjects experienced pain induced by applying capsaicin topically to the dorsal aspect of the left hand. A pain-related decrease in brain mu-OR binding was observed in the contralateral thalamus consistent with competitive binding between [11C]-carfentanil and acutely released endogenous opioid peptides. This decrease varied directly with ratings of pain intensity. These results suggest that the supraspinal mu-opioid system is activated by acute pain and thus may play a substantial role in pain processing and modulation in pain syndromes.

Topical application of clonidine relieves hyperalgesia in patients with sympathetically maintained pain.

Patients with reflex sympathetic dystrophy or causalgia characteristically have ongoing pain and pain to light touch (hyperalgesia). Some of these patients obtain relief of their pain following interruption of sympathetic function to the affected area and, therefore, have sympathetically maintained pain (SMP). Evidence suggests that the pain and hyperalgesia in SMP are related to activation of peripheral adrenergic receptors. We wished to determine the contribution of alpha 1- and alpha 2-adrenergic receptors in SMP and thus examined the effects of local application of adrenergic agents in patients with SMP. The alpha 2-adrenergic agonist clonidine, available as a transdermal patch, was delivered topically to the patients' hyperalgesic skin. In four patients with SMP, clonidine eliminated or substantially reduced hyperalgesia to mechanical and cold stimuli. In three of these patients the effects were confined to the skin region beneath the patch, suggesting a peripheral and not central effect. The relief of hyperalgesia was not due to a local anesthetic effect since touch thresholds were unaffected. Topical clonidine did not relieve hyperalgesia of similar severity for two other patients whose hyperalgesia and pain were unaffected by sympathetic ganglion blocks (i.e., diagnosed as having sympathetically independent pain). In two SMP patients, intradermal injection of norepinephrine or phenylephrine (a specific alpha 1-adrenergic agonist) at a site treated with clonidine evoked intense pain and rekindled the pre-clonidine hyperalgesia at that site. It is likely that clonidine locally blocks the release of norepinephrine via activation of alpha 2 receptors on the sympathetic terminals. This study suggests, therefore, that SMP is mediated via alpha 1-adrenergic receptors located in the affected tissue.

Spatial mapping of the zone of secondary hyperalgesia reveals a gradual decline of pain with distance but sharp borders.

The purpose of this study was to examine how pain to punctate mechanical stimuli varies with position within the zone of secondary hyperalgesia. Secondary hyperalgesia was produced by an intradermal injection of capsaicin (50 microg) into the volar forearm of human volunteers (n=9). Before and at 20, 60 and 100 min after the capsaicin injection, a computer-controlled electromechanical stimulator was used to deliver controlled-force stimuli to the skin via a 12-mm wide, 100-microm thick blade probe. Three forces (16, 32 and 64 g; 1 s) were each applied in a random order to 10 sites spaced in 1-cm increments along a line starting 1 cm from the injection site and ending near the wrist. At 40 and 80 min after capsaicin injection the 'zone of hyperalgesia' was determined with use of a hand-held 20-g von Frey probe. Whereas, before capsaicin, the blade probe produced little or no pain, after capsaicin the 32-g and 64-g stimuli evoked pain consistently within but not outside the border of secondary hyperalgesia determined with the von Frey probe. Within the zone of hyperalgesia the average pain ratings to the 64-g stimulus decreased exponentially with distance from the injection site. Surprisingly, the space constant for this exponential decay was large (about 18 cm), and thus the decrease in pain ratings from the center to the edge of the secondary zone was small (37%). However, pain ratings dropped precipitously just outside the zone of secondary hyperalgesia. This finding unlikely reflects a ceiling effect because pain ratings within the zone of secondary hyperalgesia increased linearly with force. The relatively uniform pain ratings to the blade stimuli within the zone of secondary hyperalgesia and the sharp border that delimits the zone of hyperalgesia indicate that this sensory disturbance approaches being an 'all-or-nothing' phenomenon. Thus, a two-state model for central plasticity is needed to explain secondary hyperalgesia.

Nerve injury associated with laparoscopic inguinal herniorrhaphy.

BACKGROUND: As laparoscopic herniorrhaphy becomes more popular, it is important to realize the potential for injury to surrounding neural structures, with attendant severe disability. METHODS: Herein are discussed two patients with disabling neuralgia after laparoscopic herniorrhaphy. RESULTS: Both patients were treated with transabdominal removal of their prosthetic materials and anchoring staples, with dramatic symptomatic improvement. CONCLUSIONS: The surgeon should be aware of the anatomic considerations accompanying laparoscopic herniorrhaphy. In regard to nerve injury, laparoscopic herniorrhaphy may pose certain disadvantages over traditional hernia repairs. It may diminish the ability to appreciate the course of nerves in the inguinal region and their relationship to the spermatic cord, and injury to nerves may be difficult to recognize and treat.

An electromechanical stimulator system for neurophysiological and psychophysical studies of pain.

We have developed a computer-based electromechanical stimulator system suited for neurophysiological and psychophysical studies of pain. The core of the stimulator is a servo-controlled linear motor capable of generating 1 kg of force over a 22-mm range. Forces collinear and tangenital to the interchangeable probe tip are calculated using the signal from 3 load cells (resolution: 1/8 g; range: 250 g) arranged in an equilateral triangle. Probe position is measured with an optical encoder (resolution: 1 micron; range: 25 mm). A microprocessor-based digital control system permits smooth switching of feedback control between force or position at the 1-kHz update rate. The stimulator is mounted on a microprocessor-controlled 3-axis translation system that allows automatic movement of the probe over a range of greater than 15 cm to an accuracy of better than 10 microns. The stimulator can be programmed to move in a coordinate system parallel to the skin surface being examined. An IBM-compatible computer is used to command stimulus paradigms and to display real-time motor performance and neural spike-train data. The system has been used to measure the response of nociceptive afferents in monkey to controlled force stimuli applied to various positions within the receptive field.

Latency to detection of first pain.

The latency to detection of heat stimuli applied to the distal forearm and thenar eminence was measured in 3 subjects in order to determine whether short latency responses correlated with perception of first pain. Only one temperature was used in a given run and stimuli ranged from 39 to 51 degrees C. In addition, subjects were interviewed at the end of each run regarding the quality of sensations experienced. In one series of experiments the quality of the first sensation evoked by each stimulus rather than latency was recorded. The median response latency decreased exponentially from 1100 ms to 400 ms for the distal arm and 1100 ms to 700 ms for the hand. The higher temperatures elicited a double pain sensation on the arm, but not on the glabrous hand. Warmth was always the first sensation felt on the hand. It is concluded that short latencies (less than 450 ms) reliably denote the presence of first pain, and that at least some portion of the primary afferents that signal first pain must have conduction velocities greater than 6 m/s.

A novel electrophysiological technique for locating cutaneous nociceptive and chemospecific receptors.

Conventional electrophysiological techniques for locating a cutaneous nociceptive receptor involve squeezing of the skin in the distribution of the nerve. A novel technique for locating nociceptive and chemospecific receptors has been developed, based on the coupling of action potential activity that occurs between two unmyelinated fibers in the peripheral nerve. Application of a punctate cold probe to the skin increases the latency of the coupled action potential when it is placed on the receptive field of the cutaneous receptor. More than half of the receptors which were located using this technique did not respond to mechanical or heat stimuli and therefore would not have been found using the standard search technique. Preliminary evidence suggests that some of these non-mechano-heat-sensitive receptors may be chemospecific receptors.

Evidence for two distinct classes of unmyelinated nociceptive afferents in monkey.

Unmyelinated nociceptive afferents, responsive to intense mechanical and heat stimuli, exhibited either a quickly adapting or slowly adapting response to step increases in skin temperature. These two classes of C fibers were found to differ also in other properties. The quickly adapting C fibers had significantly lower thresholds to mechanical and heat stimuli, and smaller receptive field areas than the slowly adapting C fibers.

Coupling between unmyelinated peripheral nerve fibers does not involve sympathetic efferent fibers.

Bidirectional coupling of action potential activity between unmyelinated fibers in the normal peripheral nerve of monkey has recently been reported. Often typical C-fiber nociceptors are identified with the coupled fibers. In this study, sympathetic stimulation and sympathetic ablation experiments demonstrated that the sympathetic nervous system is not involved in this coupling.

Antidromic nerve stimulation in monkey does not sensitize unmyelinated nociceptors to heat.

Spread of sensitization of nociceptors has been proposed as the mechanism for the secondary hyperalgesia in the region that surrounds a cutaneous injury. One possibility, tested in this study, is that antidromically propagated action potentials in nociceptors result in the release of substances at their cutaneous arborization which sensitize adjacent nociceptors. Using standard teased-fiber techniques, we recorded from single C-fiber nociceptive afferents innervating hairy skin in the monkey. Heat testing was performed before and after electrical stimulation of the parent nerve at strengths sufficient to activate C-fibers. The heat thresholds and total response to the heat sequences were not changed by the electrical stimulation. We conclude that antidromic stimulation of C-fibers in the monkey does not sensitize C-fiber nociceptors to heat stimuli.