The role of the dorsolateral funiculi in the pain relieving effect of spinal cord stimulation: a study in a rat model of neuropathic pain.

Activation of the dorsal columns is relayed to supraspinal centers, involved in pain modulation, probably via the descending fibers in the dorsolateral funiculi (DLF). The present study examines the role of the DLF in the attenuation of pain-related signs by spinal cord stimulation (SCS). Several groups of rats were subjected to nerve injury and to chronic bilateral DLF lesions at C5-7 level. In each animal, two sets of miniature electrodes were implanted, a caudal system placed in the dorsal epidural space at low thoracic level and another implanted over the dorsal column nuclei, rostral to the lesions. Stimulation (50 Hz, 0.2 ms; 70 % of motor threshold) was applied for 5 min via either of the electrodes. Behavioral tests were used to assess the effects of SCS on the nerve injury-induced mechanical and cold hypersensitivity and heat hyperalgesia. Prior to application of SCS, antagonists to either of GABAA or B, 5-HT1 or 1-2 or α/ß-adrenergic receptors were injected i.p. Both stimulations produced comparable decreases (80-90 % of the control) of neuropathic manifestations in rats with intact spinal cords. DLF lesions attenuated the effects of both types of stimulation by about 50 %. Pretreatment with receptor antagonists differentially counteracted the effects of rostral and caudal stimulation; the inhibition with rostral stimulation generally being more prominently influenced. These results provide further support to the notion of important involvement of brainstem pain modulating centers in the effects of SCS. A major component of the inhibitory spinal-supraspinal-spinal loop is mediated by fibers running in the DLF.

Modified technique for the exposure of the inferior alveolar nerve in rats.

The inferior alveolar nerve (IAN), a branch of the mandibular division of the trigeminal nerve, is a major component of the neurovascular bundle along with the inferior alveolar artery and vein. In rats, when exposed using an external oral approach while remaining intact, it can serve as an important tool to study the different effects of neuromediators and assess the role of different groups of nerve fibers. This paper describes a new technique to expose this nerve giving some experimental results to support its usefulness.

Spinal segmental and supraspinal mechanisms underlying the pain-relieving effects of spinal cord stimulation: an experimental study in a rat model of neuropathy.

Spinal cord stimulation (SCS) may alleviate certain forms of neuropathic pain; its mechanisms of action are, however, not fully understood. Previous studies have mainly been focused onto segmental spinal mechanisms, though there is evidence indicating a supraspinal involvement. This study aims to evaluate the relative importance of segmental and supraspinal mechanisms related to the activation of the dorsal columns (DCs). Rats were used to induce the spared nerve injury neuropathy and simultaneously subjected to chronic bilateral DC lesions at the C6-C8 level. Two pairs of miniature electrodes were implanted in each animal, with a monopolar system placed in the dorsal epidural space at a low thoracic level (below lesion) and a bipolar system placed onto the dorsal column nuclei (above lesion). Stimulation (50 Hz, 0.2 ms, 2-4V, 5 min) was applied via either type of electrodes, and tests for sensitivity to tactile and thermal stimuli were used to assess its inhibitory effects. Various receptor antagonists {bicuculline (GABA(A)), saclofen (GABA(B)), ketanserine (5HT(2)), methysergide (5HT(1-2)), phentolamine (α-adrenergic), propranolol (ß-adrenergic), sulpiride (D(2)/D(3) dopamine) or saline were injected prior to the SCS. Rostral and caudal stimulations produced a comparable inhibition of neuropathic manifestations, and these effects were attenuated by about 50% after DC lesions. Pretreatment with the various receptor antagonists differentially influenced the effects of rostral and caudal stimulation. Our findings suggest that both supraspinal and segmental mechanisms are activated by SCS, and that in this model with DC lesions, rostral and caudal stimulations may activate different synaptic circuitries and transmitter systems.

Reversible attenuation of neuropathic-like manifestations in rats by lesions or local blocks of the intralaminar or the medial thalamic nuclei.

BACKGROUND AND AIM: Thalamic somatosensory nuclei have been classified into medial and lateral systems based on their role in nociception. An imbalance between these two systems may result in abnormal somatic sensations and spontaneous pain. This study aims to investigate the effects of transient or permanent block of the medial and intralaminar nuclear groups on the neuropathic-like behavior in a rat model for mononeuropathy. METHODS: Neuropathy was induced on one hind paw in different groups of rats following the spared nerve injury model. When the resulting hyperalgesia and allodynia (tactile and cold) reached a maximum plateau, the rats received either chemical or electrolytic lesion or lidocaine (2%) microperfusion, placed in the various thalamic nuclear groups. RESULTS: All procedures produced transient but significant decrease of neuropathic manifestations. The magnitude and duration of decrease depended on the type and the site of the block. These effects can be ranked in increasing order as follows, electrolytic

Transient attenuation of neuropathic manifestations in rats following lesion or reversible block of the lateral thalamic somatosensory nuclei.

BACKGROUND AND AIMS: Nociceptive behavior in animal models for mononeuropathy has been shown to be altered by spinal tract lesions which suggest a possible supraspinal modulation. The thalamus constitutes a chief center for the processing of nociception. We have, therefore, investigated the effects of transient or permanent blocks of the lateral somatosensory thalamic nuclei (the ventrobasal complex) on the neuropathic manifestations in rats. METHODS: Different groups of rats (n = 5-6) were subjected to mononeuropathy, following the spared nerve injury model, known to produce sustained heat hyperalgesia and tactile and cold allodynia which peaked about 2 weeks after nerve injury. This was followed by stereotaxic placement of either electrolytic or chemical lesions or implantation of mini osmotic pump for slow release of lidocaine in the ventrobasal complex. RESULTS: Chronic electrolytic and chemical lesions or reversible block of the lateral somatosensory thalamus produced transient (1-2 weeks) attenuation of neuropathic manifestations along with a persistent decrease of the hot plate latency. The most pronounced effect was observed on heat hyperalgesia, and the least significant and short-lived effect was observed on cold allodynia. CONCLUSION: We conclude that the lateral somatosensory thalamic complex is involved in the processing of neuropathic manifestations but cannot be considered as an obligatory or exclusive relay center for the neuropathic syndromes.

Involvement of substance P, CGRP and histamine in the hyperalgesia and cytokine upregulation induced by intraplantar injection of capsaicin in rats.

Intraplantar (i.pl.) injection of small doses of capsaicin has been shown to produce hyperalgesia and upregulation of the levels of proinflammatory cytokines. The present work aimed at investigating the possible mediation of these effects by sensory neuropeptides and mast cells. Various groups of rats received i.pl. injection of capsaicin alone or preceded by the injection of antagonists to substance P (SP), calcitonin gene-related protein (CGRP) and histamine (H1, H2) or the mast cell blocker ketotifen. All pretreatments prevented, in a dose-related manner, the capsaicin-induced hyperalgesia. The SP, H2 antagonists and ketotifen prevented the upregulation of all cytokines and nerve growth factor (NGF) levels, while the CGRP and H1 antagonists showed only attenuation of the NGF level.

Thymulin reverses inflammatory hyperalgesia and modulates the increased concentration of proinflammatory cytokines induced by i.c.v. endotoxin injection.

The immunomodulatory thymic hormone thymulin has been shown previously to possess anti-inflammatory actions in the periphery. In this study, we have examined the effect of i.c.v. injections of either endotoxin (ET) or thymulin, in separate groups of conscious rats, on pain-related behavior and cytokine levels in different areas of the brain. Furthermore, we investigated the effect of pretreatment with either i.c.v. or i.p. injections of thymulin on endotoxin-induced hyperalgesia and the effect of pretreatment with i.c.v. thymulin on endotoxin-induced up-regulation of cytokine levels. Our results demonstrate that i.c.v. injection of endotoxin (1 microg in 5 microl saline) resulted in a significant decrease in the nociceptive thresholds as assessed by different pain tests, with peak hyperalgesia at 3 h. However, thymulin at different doses, when injected (i.c.v.), had no significant effect on pain related behavior. Pretreatment (i.c.v.) with thymulin (0.1, 0.5 and 1 microg in 5 microl saline) 20 min before endotoxin (i.c.v.) injection (1 microg in 5 microl saline) reduced, in a dose dependent manner, the endotoxin-induced hyperalgesia and exerted differential effects on the up-regulated levels of cytokines in different areas of the brain. The results provide behavioral and immunochemical characterization of a rat model for intracerebral inflammation and indicates a neuroprotective role for thymulin in the CNS.

Attenuation of neuropathic manifestations by local block of the activities of the ventrolateral orbito-frontal area in the rat.

Clinical and recent imaging reports demonstrate the involvement of various cerebral prefrontal areas in the processing of pain. This has received further confirmation from animal experimentation showing an alteration of the threshold of acute nociceptive reflexes by various manipulations in the orbito-frontal cortical areas. The present study investigates the possible involvement of this area in the modulation of neuropathic manifestations in awake rats. Several groups of rats were subjected to mononeuropathy following the spared nerve injury model, known to produce evident tactile and cold allodynia and heat hyperalgesia. The activity of the ventrolateral orbital areas was selectively blocked by using either chronic or acute injection of lidocaine, electrolytic lesion, or chemical lesion with kainic acid or 6-hydroxydopamine (6-OHDA). The effects of these manipulations were compared with those following lesion of the somatic sensorimotor cortical areas. Local injection of lidocaine resulted in a reversible depression of all neuropathic manifestations while electrolytic or chemical lesions elicited transient attenuation affecting mainly the heat hyperalgesia and to a lesser extent the cold allodynia. The magnitude of the observed effects with the different procedures used can be ranked as follows: 6-OHDA

A thymulin analogue peptide with powerful inhibitory effects on pain of neurogenic origin.

The effects of a synthetic peptide analog of thymulin (PAT) were tested on nociceptive behavior in two animal models for peripheral mononeuropathy and in another two models for capsaicin-induced hyperalgesia. Treatment with PAT (0.25-25 microg/rat, i.p.) produced significant reduction of the mechanical allodynia and heat hyperalgesia in rats subjected to either chronic constriction injury (CCI) or spared nerve injury (SNI) models for mononeuropathy. Cold allodynia was moderately reduced in the CCI model. The inhibition of neuropathic manifestations peaked at 1-2 h post-treatment and disappeared in 3-4 h. Daily treatment with PAT, however, produced progressive attenuation of all neuropathic manifestations in the SNI model. On the other hand, pretreatment with similar doses of PAT produced dose-dependent reduction of the hyperalgesia induced by intraplantar injection of capsaicin (10 microg in 50 microl). The highest dose of PAT (50 microg) produced significant reduction of abdominal aversive behavior induced by i.p injection of capsaicin (20 microg in 100 microl). Compared with the effects of treatment with morphine or meloxicam (injected at single doses known to produce analgesia), PAT exerted equal or stronger inhibitory effects on neuropathic manifestations. The reported results suggest a possible direct action of PAT on afferent nerve fibers but its mechanisms remain to be determined.

Upregulation of proinflammatory cytokines and nerve growth factor by intraplantar injection of capsaicin in rats.

Capsaicin-sensitive primary afferents (CSPA) are known to be involved in nociception and neurogenic inflammation. Extensive research has been devoted to the sensory role of these fibres but less attention has been paid to their local effector function. This study aimed at gaining more insight into the molecular mechanisms underlying the neurogenic inflammation induced by this special group of afferent fibres. Different groups of rats (n = 5 in each group), either naive or subjected to selective ablation of their CSPA, received individual intraplantar injections of saline, capsaicin, its vehicle or capsaicin preceded by its antagonist, capsazepine. Acute tests for nociception were used to assess the variations of the nociceptive thresholds. Variations of the levels of proinflammatory cytokines and nerve growth factor (NGF) were measured by enzyme-linked immunosorbent assay (ELISA). Intraplantar injection of capsaicin (10 microg in 50 microl) produced a sustained thermal and mechanical hyperalgesia that peaked at 3-6 h and disappeared 24 h following the injection. Similar capsaicin injection in further groups of rats produced an early upregulation of the proinflammatory cytokines and NGF, which peaked at 30-60 min and returned to control levels within 2-5 h. Similar effects were observed following the application of either capsaicin or intense electrical stimulation on the cut end of the distal portion of the sciatic nerve. The effects of capsaicin were abolished in rats subjected to selective ablation of their CSPA. These results demonstrate that CSPA can simultaneously challenge the immune system through the release of proinflammatory mediators and the central nervous system through nociceptive signalling and can therefore serve as a common afferent pathway to both immune and nervous systems.

The role of the dorsal columns in neuropathic behavior: evidence for plasticity and non-specificity.

Despite conflicting clinical and experimental evidence, textbook description of somatic sensations continues to follow a rigid dichotomy based on the concept that pain sensation is transmitted cephalad primarily through anterolateral pathways, while touch is mediated through the dorsal column pathway. This study provides an example of the dynamic rerouting in the transmission of the nociceptive signals following injuries to the peripheral and central processes of sensory neurons. In two rat models for mononeuropathy, the chronic constriction injury model [Bennett, G.J., Xie, Y.K., Pain 33 (1988) 87-107] and the spared nerve injury model [Decosterd, I., Woolf, C.J., Pain 87 (2000) 149-158], we demonstrate that selective dorsal columns lesion produced significant decrease of tactile and cold allodynias and thermal hyperalgesia which were assessed by the Von Frey hair filaments, the acetone drop test and the heat-induced paw withdrawal, respectively. These manifestations, however, can reappear 2 weeks after bilateral dorsal column lesion in rats subjected to spared nerve injury mononeuropathy and appear also in animals sustaining chronic bilateral dorsal column lesion followed by either model of mononeuropathy. Lesion of the dorsal column on the side opposite to the neuropathic leg did not alter the neuropathic manifestations in both animal models. Changes in the sequence of timing of the dorsal column lesion and induction of mononeuropathy, suggest that the effects of the former last for 1 to 2 weeks. The results of this study show that the dorsal columns are involved in neuropathic manifestations and at the same time are not necessary for their full development and persistence. Furthermore, these results shade doubts on the validity of the concept of segregation of pathways involved in the transmission of neuropathic manifestations. Therefore, principles governing acute pain transmission are not necessarily applicable to chronic pain situations. The latter conditions seem to engage other available pathways to reestablish the pain signaling system.

Attenuation of neuropathic pain by segmental and supraspinal activation of the dorsal column system in awake rats.

In addition to its involvement in the transmission of neuropathic pain, the dorsal column system has been shown to have analgesic effects when electrically stimulated. The segmental or supraspinal origin of the analgesia, however, has not been clearly delineated. The aim of this study is to demonstrate the contribution of supraspinal mechanisms to the inhibition of allodynia and hyperalgesia in two different rat models of mononeuropathy. Mononeuropathy was induced, under deep anesthesia, in several groups of rats (n=7 each) following either the chronic constriction injury or the spared nerve injury model. Mechanical and cold allodynia were assessed by the Von Frey monofilaments and by the acetone drop test, respectively. Thermal hyperalgesia was assessed by the paw withdrawal and hot plate tests. Bipolar electrodes for dorsal column stimulation were implanted chronically in all rats on the dorsal aspect of the medulla at the level of the obex. Selective dorsal column bilateral lesions were performed at the upper cervical level in some groups of rats. Dorsal column nuclear stimulation, rostral to selective dorsal spinal lesions, produced strong inhibitory effects on the allodynia and hyperalgesia observed in both models of mononeuropathy. These effects were comparable to those observed following similar stimulations in rats with an intact spinal cord. Our results demonstrate strong inhibitory effects of dorsal column stimulation on neuropathic pain. This inhibition can be attributed to the activation of brainstem pain-modulating centers via rostral projections of the dorsal column nuclei.

The role of the sympathetic efferents in endotoxin-induced localized inflammatory hyperalgesia and cytokine upregulation.

The sympathetic system (SNS) is considered to be a major component of the neurogenic contribution to inflammation and hyperalgesia. We have investigated the role of the SNS in the local inflammatory pain induced by intraplantar (i.pl) injections of bacterial endotoxin (ET). Treatment of rats with an alpha-adrenoceptor antagonist (phentolamine, 0.25-1 mg/kg, i.p.), a beta-adrenoceptor antagonist (propranolol, 1-10 mg/kg, p.o.) or a sympathetic neuron-blocking agent (guanethedine, 30 mg/kg, s.c.) resulted in a dose-dependent reduction of the thermal hyperalgesia induced by ET. Mechanical hyperalgesia, however, was less sensitive to inhibition by propranolol and guanethedine but significantly inhibited by phentolamine. ET injection produced significant upregulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, and nerve growth factor (NGF). Treatment with any one of the three sympatholytics abolished the upregulation of NGF and IL-6, while phentolamine and guanethedine also reversed the upregulation of TNF-alpha. IL-1 beta was resistant to all of the sympatholytic treatments. We conclude that the SNS can contribute to the local inflammation and hyperalgesia following injection of ET. The resistance to sympatholytics shown by IL-1 beta, known to play a key role in the inflammatory cascade, suggests that ET can initiate inflammation and hyperalgesia independently of peripheral and central sympathetic mechanisms.

A perfusion technique for the determination of pro-inflammatory mediators induced by intradental application of irritants.

INTRODUCTION: Several morphological and functional features contribute to the consideration of the tooth as a separate compartment having special type of innervation and special immune mechanisms. This study describes a new method allowing the intradental perfusion of rat incisors for the in vivo assessment of pulpal reaction to inflammatory agents. METHODS: Under deep anesthesia, the distal 2-3 mm of each of the rat lower incisors was cut and wrapped in a polyethylene tubing connected to a perfusion chamber made of tigone tubing (ID 1/8 in., volume 100-150 microl). Several groups of rats (n=5 each) were used for intradental application of either saline, capsaicin (100 microg in 100 microl), or endotoxin (ET, 20 microg in 100 microl) for a period of 40 min followed by filling the tooth chamber with saline and collecting the perfusate every 40 min for a period of 8 h. The collected perfusates were stored at -70 degrees C for subsequent determination of the concentration of prostaglandin E(2) (PGE(2)) and nerve growth factor (NGF) by enzyme-linked immunosorbent assay (ELISA). RESULTS: Dentinal injury produced a moderate increase in the levels of NGF and PGE(2) in incisors perfused with saline. Application of ET or capsaicin, however, produced a highly significant increase in the levels of both mediators. These effects peaked at 1.5-3 h for PGE(2) and at 5 h for NGF. Capsaicin showed the most significant effects. DISCUSSION: The reported results cannot be attributed to any factor other than the inflammation of the incisor's pulp, because the described chamber does not allow any spread or leak of the applied irritants. Further studies using other reagents can allow the determination of the variation of the levels of the various pro-inflammatory mediators and their modulation by treatment with anti-inflammatory drugs.

Modulation of ultraviolet-induced hyperalgesia and cytokine upregulation by interleukins 10 and 13.

1. Exposure to midrange ultraviolet radiation (UVB) is known to produce skin inflammation similar to sunburn. The aim of this study was to characterize the hyperalgesia and cytokine upregulation induced by UVB and their modulation by antiinflammatory cytokines. 2. Acute exposure of the dorsal skin of mice to UVB (200, 250 and 300 mJ cm(2)) resulted in a dose-dependent decrease in the latencies of the hot plate and tail flick tests, without evident signs of skin lesions. 3. The observed hyperalgesia displayed a biphasic temporal evolution with an acute phase (3 - 6 h) and a late (48 - 96 h) phase. 4. Exposure to UVB (300 mJ cm(2)) elicited significant upregulation of interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha and nerve growth factor (NGF), determined by ELISA in the exposed skin. This upregulation was more important during the acute phase of hyperalgesia. 5. Daily treatment of mice, with i.p. injections of either IL-10 or IL-13 (1.5, 7.5 and 15 ng in 100 microl saline) produced a dose-dependent attenuation of the UVB-induced hyperalgesia. 6. Treatment with the highest doses of either IL-10 or IL-13, produced significant attenuation of the levels of the cytokines and NGF by UVB, with relatively more pronounced effects by IL-13. 7. Acute exposure to moderate amounts of UVB results in a systemic hyperalgesia related to the upregulation of cytokine and NGF levels, since both were prevented by treatment with antiinflammatory cytokines.

The role of cytokines and prostaglandin-E(2) in thymulin induced hyperalgesia.

We have recently reported that intraperitoneal (i.p.) injection of thymulin at low doses (50 ng) resulted in thermal and mechanical hyperalgesia and upregulation of the level of interleukin-1beta in the liver. In this study, we demonstrate that such injections of thymulin result in a significant elevation in the levels of TNF-alpha (P<0.01), NGF (P<0.01) and PGE(2) (P<0.01) in the liver of the treated rats, in addition to the increase in the levels of IL-1beta. Pretreatment with specific antagonists to each of these factors (polyclonal anti-TNF-alpha, anti-NGF antiserum and IL-1 receptor antagonist) did not result in the abolition of the hyperalgesia as assessed by the paw pressure, hot plate, paw immersion and tail flick tests. However, pretreatment with a combination of the above antagonist and antisera almost completely prevented thymulin-induced hyperalgesia. The cyclooxygenase inhibitor, meloxicam, reversed in a dose dependent manner (0.2, 0.4 and 2 mg/kg) thymulin effects as assessed by the different pain tests. It also abolished the thymulin-induced increase in the level of cytokines and NGF in the liver. Our results indicate that PGE(2) could be the key mediator of the hyperalgesic action of thymulin and the observed upregulation of proinflammatory cytokines and NGF.

Inhibitory effects from various types of dorsal column and raphe magnus stimulations on nociceptive withdrawal flexion reflexes.

Most of the clinical and research reports agree about the analgesic effects of dorsal column (DC) stimulation, but there is no unanimity about the neural mechanisms involved in this stimulation. The aim of the present study was to compare the effects of segmental and rostral activation of the DCs and to investigate whether these effects are mediated through a brainstem spinal loop. Decerebrate-decerebellate cats were subjected to selective DC lesions at C(1) and C(3) spinal cervical levels and their reflex reactions to natural or electrical nociceptive stimuli were monitored either as withdrawal flexion reflexes or as motorneuronal discharges. Conditioning stimulation was performed as train of shocks (100 Hz, for 1 to 10 min or 300 Hz for 30 ms) applied on the DCs either rostral (DCr) or caudal (DCc) to the spinal lesions or on the raphe magnus (RM). Conditioning trains for 5-10 min applied on DCr inhibited the withdrawal flexion reflexes recorded as toe flexion (90% of the control). Comparisons of the effects of DCr, DCc or RM of conditioning stimuli were made on the discharges of 110 motorneurons recorded in isolated ventral root fibers. Conditioning stimulation applied to DCc produced short lived inhibition (in about 60%) or facilitation (in about 30% of the neurons) while DCr or RM conditioning produced inhibition in 90% of neurons which outlasted the duration of the conditioning trains. It was also shown that repetitive application of conditioning train on either DCr or RM resulted in longer duration of inhibition than that observed following DCc conditioning. We conclude that the stronger inhibition of motorneuronal discharges, evoked by nociceptive stimuli, is obtained by rostral activation of the DCs and that long term effects of DCst are mediated through a DC-brainstem-spinal loop.

Thymulin induces c-fos expression in the spinal cord of rats which is reversed by meloxicam and morphine.

Intraplantar (i.pl.) injections of thymulin have been shown to produce hyperalgesia in rats through a prostaglandin E2-dependent mechanism. This study aimed at investigating if such injections can produce sustained activation of spinal neurons by mapping the fos-like-immunoreactivity (FLI) as a marker for this activation. Our results showed that thymulin produces significant and sustained FLI in neurons located in spinal laminae known to be involved in nociception. Pretreatment with either morphine or meloxicam (a cyclooxygenase inhibitor) revealed differential effects on FLI and the hyperalgesia induced by thymulin. These findings support the hypothesis that thymulin can affect central neurons either directly or through the peripheral nerve terminals.

Cytokine-mediated or direct effects of thymulin on the nervous system as assessed by pain-related behavior.

Thymulin is a thymic hormone with known immunomodulatory activities. Recent evidence has indicated a signaling role for this peptide in the interaction between the immune, endocrine and the nervous system. In this report, we review recent experimental findings on the analgesic actions of thymulin (high doses) in rats with endotoxin-induced localized inflammation and the hyperalgesic actions (low doses) of this peptide in intact animals. These actions involve both proinflammatory cytokines and PGE2. The possibility of a dual role played by thymulin as a hormone that might also involve a direct effect on the nervous system is discussed.

Involvement of capsaicin sensitive primary afferents in thymulin-induced hyperalgesia.

Intraplantar (5 ng) or intraperitoneal (50 ng) injections of thymulin, produced both thermal and mechanical hyperalgesia in rats. In this report, we show that ablation of capsaicin sensitive primary afferents (CSPA) can alter or abolish thymulin-induced hyperalgesia. Different groups of rats were subjected to either treatment with capsaicin or to surgical subdiaphragmatic vagotomy (SDV). Both capsaicin and SDV reduced significantly thymulin-induced hyperalgesia. On the other hand, these treatments elicited differential effects on the modulation by thymulin of the levels of nerve growth factor and interleukin 1beta. We conclude that the hyperalgesic effects of i.p. thymulin are mainly mediated through the CSPA fibers.