Assessment of mechanical and thermal thresholds of human C nociceptors during increases in skin sympathetic nerve activity.

OBJECTIVES: The objective of the present study is to investigate the relationship between C-fiber nociceptor sensitivity and skin sympathetic nerve activity during mental arithmetic. METHODS: Single afferent C-fibers were identified simultaneously with spontaneous postganglionic sympathetic discharges and recorded from the peroneal nerve using microneurography in 23 normal subjects. Mechanical and heat thresholds were measured by 'marking' the nociceptor with suprathreshold stimuli, causing increased latency after a subsequent threshold stimulus at rest and during mental arithmetic. Skin sympathetic nerve activity was estimated by counting the number of bursts per minute. RESULTS: Thirty-two single C-fibers were identified. Eleven had polymodal receptors (mechanical and heat sensitive), eight were only sensitive to mechanical stimuli, two were only sensitive to heat stimuli, and 11 were insensitive to both. C-fibers were selected when the ratio of skin sympathetic nerve activity during mental arithmetic to that at rest was over 1.00. In 19 selected mechanical sensitive units, average mechanical threshold was 4.86 at rest and 4.84 during mental arithmetic. In 6 selected heat sensitive units, average heat threshold was 45.0 degrees C at rest and 43.4 degrees C during mental arithmetic. However, differences were not statistically significant. CONCLUSIONS: Physiological sympathetic stimulation did not affect afferent C-fiber nociceptor sensitivity to mechanical and heat stimuli in healthy subjects.     

Inflammation reduces mechanical thresholds in a population of transient receptor potential channel A1-expressing nociceptors in the rat

Inflammatory hypersensitivity is characterized by behavioural reductions in withdrawal thresholds to noxious stimuli. Although cutaneous primary afferent neurones are known to have lowered thermal thresholds in inflammation, whether their mechanical thresholds are altered remains controversial. The transient receptor potential channel A1 (TRPA1) is a receptor localized to putative nociceptive neurones and is implicated in mechanical and thermal nociception. Herein, we examined changes in the properties of single primary afferents in normal and acutely inflamed rats and determined whether specific nociceptive properties, particularly mechanical thresholds, are altered in the subpopulation of afferents that responded to the TRPA1 agonist cinnamaldehyde (TRPA1-positive afferents). TRPA1-positive afferents in normal animals belonged to the mechanonociceptive populations, many of which also responded to heat or capsaicin but only a few of which responded to cold. In acute inflammation, a greater proportion of afferents responded to cinnamaldehyde and an increased proportion of dorsal root ganglion neurones expressed TRPA1 protein. Functionally, in inflammation, TRPA1-positive afferents showed significantly reduced mechanical thresholds and enhanced activity to agonist stimulation. Inflammation altered thermal thresholds in both TRPA1-positive and TRPA1-negative afferents. Our data show that a subset of afferents is sensitized to mechanical stimulation by inflammation and that these afferents are defined by expression of TRPA1.     

Responses of neurons in the region of human thalamic principal somatic sensory nucleus to mechanical and thermal stimuli graded into the painful range.

The role of the region of the principal somatic sensory nucleus of the human thalamus (ventral caudal - Vc) in signaling painful sensations is unclear. We have now studied the response of cells (n = 57) in this region to both thermal and mechanical stimuli graded into the painful range during surgeries (n = 24) for treatment of movement disorders. Fifteen cells had a graded response to mechanical stimuli extending into the painful range and, thus, were classified in the wide dynamic range (WDR) category. The mean stimulus-response function of cells in the WDR class, normalized to baseline, showed a fourfold mean increase in firing rate above baseline across the mechanical series of stimuli. Seven of these cells responded to heat stimuli (WDR-H) and two responded to cold stimuli (WDR-C). Twenty-five cells were in a class (multiple receptive - MR) that showed a response to both brush and compressive stimuli, although the responses were not graded into the painful range. Three of these cells (MR-H) had a response to heat stimuli and five cells responded to cold stimuli (MR-C). Nine cells responded to brushing without a response to the compressive stimuli (low threshold - LT). Cells responsive to painful mechanical and thermal stimuli were located throughout the thalamic region where cells responded to nonpainful cutaneous stimulation. These results show that cells in the region of the human thalamic principal somatic sensory nucleus respond to mechanical and thermal stimuli extending into the painful range.     

Sensory functions in chronic neuralgia.

Eleven patients with sustained neuralgia, in most cases after traumatic nerve lesion, were subjected to quantitative sensory testing with thermal and non-noxious mechanical stimuli. Measurements were made in the pain area and at a homologous site on the contralateral normal side. All patients were hypoaesthetic with raised thresholds for warm and cold or touch, or both. Thermal pain thresholds were also raised in some patients but lowered in others indicating hypersensitivity of the nociceptor system or dysaesthesia for thermal input. In six patients single mechanical stimuli produced a painful response above the touch detection threshold. Reaction time measurements indicated that this painful response to suprathreshold mechanical pulses was measured by magnitude estimation as a function of stimulus amplitude. The results were fitted by power functions, as in normal skin, but with steeper slopes on the abnormal side. Suprathreshold hyperaesthesia (recruitment) may exist in the presence of normal threshold functioning.     

Postsynaptic dorsal column pathway of the rat. II. Evidence against an important role in nociception

The response characteristics of neurons at the origin of the postsynaptic dorsal column (PSDC) pathway were determined in unanesthetized, decerebrated, spinalized rats. Sixty-four percent of PSDC neurons responded only to innocuous mechanical stimuli. Thirty-six percent responded to innocuous stimuli but were more powerfully activated by noxious pinch. Ninety-three percent of the tested PSDC neurons were not activated by any of several intensities of sustained, repeated noxious heating of their receptive fields. The failure of pinch-responsive PSDC cells to respond to thermal stimulation, even in sensitized skin, suggests that they do not receive a functionally significant input from C polymodal nociceptors, heat nociceptors, or mechanical-heat nociceptors. We conclude, therefore, that the postsynaptic dorsal column pathway is not importantly involved in nociception in the rat.     

Dorsal column postsynaptic neurons in the cat are excited by myelinated nociceptors

Some (25-50%) dorsal column postsynaptic (DCPS) neurons respond only to innocuous mechanical stimuli; the remainder (50-75%) responds to both innocuous and noxious mechanical stimuli. Those that respond to noxious mechanical stimuli (pinch) are assumed to be excited by input from nociceptive primary afferents, but it is conceivable that their pinch-evoked responses are produced by the inadvertent activation of those low-threshold mechanoreceptive primary afferents that respond to stretching the skin. Because nociceptive primary afferents respond reliably to noxious heat and low-threshold mechanoreceptors do not, we tested DCPS neurons in the cat lumbar spinal cord with a series of noxious heat stimuli (48 degrees C or 50 degrees C-56 degrees C; 30 s duration). Seven of eight pinch-responsive neurons responded to noxious heat, but only after their receptive fields had been sensitized by prolonged or repeated heating. The results show that (1) many DCPS neurons in the cat are excited by nociceptive primary afferents and (2) these nociceptive afferents are probably myelinated high-threshold mechanoreceptors.     

Properties of functionally identified nociceptive and nonnociceptive facial primary afferents and presynaptic excitability changes induced in their brain stem endings by raphe and orofacial stimuli in cats

The activity of 221 single primary afferent units was recorded extracellularly in the trigeminal (V) ganglion of chloralose-anaesthetized cats to examine the receptive field properties of nonnociceptive and nociceptive cutaneous afferents and the effect of conditioning stimulation of the raphe system and orofacial afferents on the antidromic excitability of their brain stem endings in V subnucleus caudalis. In addition to slowly adapting and rapidly adapting low-threshold mechanosensitive afferents, we functionally identified three classes of cutaneous nociceptive afferents: these included A-delta high-threshold mechanoreceptive afferents (A-delta HTMs), C-fiber high-threshold mechanoreceptive afferents (C-HTMs), and C-polymodal nociceptive afferents (CPNs). Most of the CPNs could be activated by light tactile stimuli as well as by heavy pressure and pinch and noxious radiant heat applied to their mechanoreceptive field which usually involved a localized spot (approximately 1 mm in diameter) of skin. In contrast, the C-HTMs and A-delta HTMs could not be activated by radiant heat stimuli although some did show sensitization which was also a feature of the CPNs; they did respond to noxious mechanical stimulation of a localized area of skin. We noted that orofacial conditioning stimulation could produce an increase in antidromic excitability which was considered a reflection of primary afferent depolarization (PAD) in both nociceptive and nonnociceptive afferents innervating the cat's facial skin; nonnoxious mechanical stimuli and electrical stimuli were particularly effective in the low-threshold mechanosensitive afferents and noxious mechanical and high-intensity electrical stimuli were especially effective in the cutaneous nociceptive afferents. Raphe conditioning stimulation also was very effective in inducing PAD in these nociceptive afferents; however, the raphe conditioning effects were not limited to these nociceptive afferents since PAD was also frequently demonstrated in the low-threshold mechanosensitive afferents.     

Does neurogenic inflammation alter the sensitivity of unmyelinated nociceptors in the rat?

This study on neurogenic inflammation aimed at comparing the effects of antidromic nerve stimulation and of cutaneous application of mustard oil on the mechanical and thermal sensitivity of cutaneous C-fibres in the rat saphenous nerve. They were tested with von Frey hairs and series of radiant heat stimuli in 5-min intervals before and after one of the above treatments. Antidromic electrical stimulation was effective in evoking a plasma extravasation in the saphenous region as revealed by prior intravenous injection of Evans blue. However, it did not evoke spontaneous activity in the polymodal C-fibres tested nor did it markedly affect their mechanical and thermal excitability in periods of up to 1 h after stimulation. Mustard oil, topically applied to the receptive fields, also evoked localized Evans blue extravasation and strongly affected the C-units. They responded to the application of the irritant with sustained firing; most units showed an increased thermal sensitivity after the treatment. This involved a lowering of the threshold and an increase of the suprathreshold discharge. Even low threshold mechanosensitive C-fibres transiently developed heat sensitivity. In some polymodal units a transient sensitization was followed by a persistent desensitization which abolished their thermal and mechanical sensitivity. Mustard oil application and antidromic nerve stimulation seem to be similar in evoking cutaneous vasodilatation and plasma extravasation but different in inducing nociceptor sensitization.     

Paradoxical heat sensations during moderate cooling of the skin

Paradoxical heat sensations during cooling of the skin were examined in two experiments. In Expt. I the number of occurrences of sensation was studied in 19 naive test subjects (Ss) when cooling from thermal indifference both without and with preceding heating. Without preceding heating 13 Ss reported sensations of paradoxical heat (9.8% of all stimulations). Preheating markedly facilitated the occurrence of the sensations (35% of all stimulations). In Expt. II the effects of cooling velocity (velocities 0.4, 0.7 and 2.0 °C/s) and the type of skin area stimulated (hairy or glabrous skin of the hand) on the thresholds of paradoxical sensations were studied in 4 Ss without and with preheating. Cooling velocity, type of skin area and preheatting had significant effects on the sensation thresholds, the thresholds being the higher (i.e. the sensation appearing at lower stimulation temperatures) the higher the cooling velocity, if the stimuli were applied to the glabrous skin, or if no preheating was used. The results confirm the existence of paradoxical heat sensations during cooling of the skin and suggest that thesensation is mediated by polymodal units supplied by C-fibers.     

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.     

Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy.

In the present study we have used a recent rat model for neuropathic pain to investigate the effect of the sympatholytic drug guanethidine on changes in behavioural responses evoked by mechanical, heat and cold stimuli and on self-mutilating behaviour. After a unilateral peripheral mononeuropathy induced by ligatures around the right common sciatic nerve, the left side receiving just a sham wound, lesioned and non-operated control animals were treated with saline or guanethidine (30 mg/kg) for 4 consecutive days commencing 5 days before or 10 days after surgery. Behavioural parameters were followed for 4 weeks after drug treatment. Lesioned rats were found to be sensitized to the otherwise innocuous cold stimulus and showed decreased response thresholds to noxious heat and mechanical stimuli. Some lesioned animals self-mutilated. Treatment with guanethidine diminished heat and cold sensitization considerably, but had less effect on mechanical sensitization and, if administered before surgery, rather increased the severity of self-mutilating behaviour. While these results are in agreement with clinical observations on the prominence of sensitization to evoked stimuli, especially cold, and the effectiveness of guanethidine in sympathetically maintained neuropathic pain, they indicate that the mechanisms involved in sensitization to different stimuli and self mutilating behaviour differ.     

Variability of sensory threshold determination in clinical use

The variability of perception threshold determination for vibration, tactile stimuli and thermal stimuli, with instruments intended for clinical use, was studied in 13 healthy subjects and 27 patients with chronic polyneuropathy. Normal thresholds for tactile and thermal stimuli were determined in 51 healthy subjects. Determinations were made for vibration on hand, lower leg and foot, for touch on pulp of forefinger and great toe and for temperature on hand and foot. Normal thresholds for both tactile and thermal stimuli were age-dependent. Short-term variation, with intervals of some minutes between determinations, remained within 8–18% change from first value. Long-term variation, with intervals of days to some weeks, was pronounced for all types of threshold, with extremes of ?90% and +256% change from first determination in 3 or 4 subsequent determinations. Variation was most marked for tactile stimuli and smallest for vibration, but magnitude and pattern of variation was similar for all sensory modalities and for both patients and healthy subjects. Confidence intervals, derived from analysis of variance, showed that as an average a change of < ?60% or > + 150% from the initial value was needed to ascertain with 95% probability that a subsequent value will reflect a true change of sensory threshold. Basing every threshold value on 2 or more measurements per occasion will reduce the confidence interval.The main cause of variability seems to be central processing mechanisms, i.e. the psychological variability. With proper attention to the variability, sensory threshold determinations should still be a valuable aid in clinical practice and clinical research.     

Hyperexcitable polymodal and insensitive nociceptors in painful human neuropathy

Six patients with chronic pain, mechanical and thermal hyperalgesia/allodynia, and cutaneous vasodilatation starting distally in their extremities, were evaluated using clinical and neurophysiological methods and microneurography. Evidence of small-fiber polyneuropathy was documented in all, but the etiology remained cryptogenic in several. Different forms of hyperexcitability were detected by microneurography in both common polymodal and mechanically insensitive C nociceptors, which explain all the somatosensory abnormalities. Signs of hyperexcitability included reduced receptor threshold (accounting for mechanical and heat allodynias), spontaneous C nociceptor discharge (explaining spontaneous "burning" pain and antidromic vasodilatation), and multiplied nociceptor responses to stimulation (accounting for hyperalgesia). The clinical and electrophysiological profiles of these patients resemble the experimental syndrome evoked by application of capsaicin to the skin. This similarity, and the striking heat dependence of the spontaneous pain, suggest that a common feature may be altered expression or modulation of vanilloid 1 receptor, provoking abnormal nociceptor discharges.     

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.     

Platelet contribution to leukotriene production in inflammation: in vivo evidence in the rabbit

The contribution of platelets to arachidonic acid transcellular metabolism may represent an important pathway of leukotriene (LT) production. The aim of this study was to investigate the role of platelets on LT production in an acute inflammatory model in the rabbit. Preliminary experiments showed that rabbit whole blood (5 ml) stimulated in vitro with the calcium ionophore A23187 produced LTB4 (52.7+/-13.9 ng) and the mixed 5,12-DiHETE (7.25+/-0.75 ng). In A23187-stimulated thrombocytopenic blood, LTB4 was significantly reduced to 19.5+/-8.6 ng and 5,12-DiHETE was undetectable. Peptido-LTs were undetectable in both conditions. In experiments using washed cells, addition of thrombin-activated platelets to fMLP-activated PMN resulted in the appearance of 5,12-DiHETE and in more than twofold increase of LTB4 synthesis. When 3H-arachidonic acid-labelled platelets were mixed with unlabelled PMN and challenged with fMLP and thrombin, radioactive LTB4 and 5,12-DiHETE were produced, indicating that platelet-derived arachidonic acid was utilized by PMN 5-lipoxygenase. Intravenous infusion of fMLP (2.5 nmol/kg/min) in the rabbit induced marked granulocytopenia, thrombocytopenia and increased TxB2 plasma concentrations within 3 min. Electron microscopy of lungs showed morphologically activated and aggregated platelets occluding the capillary lumen. Activation and recruitment of circulating cells was accompanied by the production of LTB4 (peak levels at 1 min: 30.0+/-9.5 ng/ml) and LTE4 (peak levels at 10 minutes: 77.8+/-11.6 ng/ml). The areas under the blood concentration-time curve (AUC, ng min/ml) corresponded to 812+/-182 and 3692+/-658 for LTB4 and LTE4, respectively. In immunologically thrombocytopenic rabbits, the AUC for LTB4 (86.0+/-23.0) and LTE4 (1165+/-542) were both significantly different from controls while in rabbits treated with an anti-leukocyte antiserum, both LTB4 and LTE4 were similar to controls. This experimental model provides in vivo evidence that platelets, involved in an acute inflammatory event contribute to the transcellular production of LTs.     

Substance P and somatostatin modulate spinal cord excitability via physiologically different sensory pathways

The effect of intrathecally injected substance P and somatostatin on spinal flexion reflex excitability was examined in decerebrate, spinalized, unanaesthetized rats. Substance P increased the excitability of the spinal cord to mechanical and thermal stimuli suprathreshold for C-afferents. Somatostatin had a similar effect with thermal, but not with mechanical stimuli. It is suggested that both peptides are released in association with C-afferent activation. Substance P may be released by polymodal nociceptors whereas somatostatin may be released by thermosensitive C-afferents.     

Reproducibility and influence of test modality order on thermal perception and thermal pain thresholds in quantitative sensory testing

Objective

To evaluate the reproducibility of quantitative sensory testing (QST), performed with the method-of-limits (MLI) at different test intervals, by assessing the inter- and intra-individual variation of thermal cold (CT) and warm (WT) perception thresholds, and of thermal cold- (CPT) and heat pain (HPT) thresholds.

Methods

QST with the MLI was performed in 38 healthy subjects in three repeated and pseudo-randomized test sessions, done at three occasions (days 1, 2 and 7).

Results

At repeated testing, none of the thermal threshold estimates showed systematic significant differences, neither between days nor between sessions within the same day, when determined as first tests (FT), and for CT and WT also after thermal pain assessment (aTPA). However, when determined directly aTPA, both CT and WT were noted significantly higher. Also the coefficients of variation and repeatability showed increased values aTPA.

Conclusions

The high reproducibility show that the MLI is a feasible method for thermal QST, with reproducible results both at shorter and longer test intervals, on condition that temperature thresholds are determined before any painful thermal stimuli are given, as the latter influence both CT and WT assessments.

Significance

The findings show that QST with the MLI is a reliable tool for indirect evaluation of human small nerve fiber function.     

Unmyelinated nociceptive units in two skin areas of the rat

Responses of unmyelinated afferent fibres were investigated in two skin nerves of Sprague-Dawley rats. The units were tested as to whether they responded to mechanical probing of the skin, to controlled radiant heat stimulation, and/or to cooling of the skin(to 5°C). Ninety-six units in a n. saphenus and 129 units in a n. coccygealis werre studied, which were identified as afferents by means of the above-mentioned stimuli. In both nerves mechano- and heat-sensitive units (CMHs) were most frequent (56% in n. saphenus and 74% in n. coccygealis). There were, however, significantly more purely mechanoceptive units (CMs) in n. saphenus than in n. coccygealis (30% vs 5%). In contrast cold-sensitive units (CCs) were more frequent in n. coccygealis. They constituted 25% of the afferent C-fibres in this nerve. When testing heat sensitivity of CMHs with ramp stimuli raising the temperature to 55°C at a rate of 0.8°C/s, heat thresholds had a wide range of between 30 and 55°C. Since CMHs with low heat thresholds had the highest discharge rates and the greatest dynamic sensitivity in the range of noxious temperatures, they most probably also had nociceptive functions. It was shown that the low heat thresholds of some CMHs were not due to sensitization by preceding heat stimuli. It is argued that low-frequency discharges ( 2Hz) observed in some nociceptive CMHs of the rat at nonnoxious temperatures are insignificant for nociception. When comparing discharges during a first ramp heat stimulus to 50°C (rise time 1°C/s) with those during a second stimulus of identical time course delivered 5–10 min later, 44% of the CMHs were sensitized, 24% were desensitized and the remainder were not clearly influeced. We did not find a significant correlation between initial heat thresholds and tendency to sensitization or desensitization.     

Characterization of mechanical withdrawal responses and effects of mu-, delta- and kappa-opioid agonists in normal and mu-opioid receptor knockout mice

Clinical and experimental observations suggest that opiates can exert different influences on the perception of stimuli from distinct sensory modalities. Thermally-induced nociception is classically responsive to opiate agonists. mu-Opioid receptor-deficient transgenic mice are more sensitive to thermal nociceptive stimuli and morphine fails to attenuate the nociceptive responses to thermal stimuli in these animals. To enhance our understanding of opiate influences on mechanical sensitivity, we have examined withdrawal responses to a sequence of ascending forces of mechanical stimuli in mice with normal (wild type), half-normal (heterozygous) and absent (homozygous) mu-opioid receptor levels. We report data from mice examined without drug pretreatment or following pretreatment with morphine, the selective kappa-opioid agonist, U50488H, and the selective delta-opioid agonist, DPDPE. Saline-pretreated mice of each genotype displayed similar, monotonically increasing frequency of withdrawal responses to the graded stimuli. Subcutaneously administered morphine produced a dose-dependent reduction in withdrawal responses in wild type and heterozygous mice, but had no significant effect in homozygous mice. Intraventricular administration of DPDPE also reduced the frequency of paw withdrawal (FPW) in wild type mice, but not in homozygous mice. In contrast, systemic U50488H produced a dose-dependent attenuation of paw withdrawal in both wild type and homozygous mice. These findings suggest that (1) interactions of endogenous peptides with mu-opioid receptors may not play a significant role in the response to mechanical stimuli in drug-free animals, and (2) deficiency of mu-opioid receptors has no functional consequence on the response to the prototypical kappa-opioid receptor agonist, but decreases responses to the prototypical mu- and delta-opioid receptor agonists.     

Epineurial application of TNF elicits an acute mechanical hyperalgesia in the awake rat

Abstract   Tumor necrosis factor alpha (TNF) injected into the sciatic nerve and neutralizing antibodies to its receptor injected around the nerve are respectively associated with inducing and blocking pain behavior beginning 1 to 3 days post-injection. This study examined the acute effects of TNF applied around the nerve trunk on the mechanical threshold (determined with von Frey hairs) and withdrawal latency to radiant heat. TNF (0.9 and 7.7 ng in 90 μL) injected onto the nerve via an indwelling catheter elicited a decrease in mechanical threshold. Following the low dose of TNF, no change in thermal latency was observed; after the 7.7 ng dose, thermal thresholds decreased and returned to baseline multiple times within the 3-hour observation period. Identical doses of TNF injected near, but not on the nerve, 90 ng of TNF injected on the nerve, and vehicle were without effect on either modality. These data indicate that effects of acutely administered TNF to the nerve trunk are capable of producing modality specific pain behavior. These changes may represent a first step in TNF-induced neuropathic pain.