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PubMed1994

Influence of various experimental parameters on the incidence of thermal and mechanical hyperalgesia induced by a constriction mononeuropathy of the sciatic nerve in lightly anesthetized rats.

In the current investigation we examined a peripheral mononeuropathy induced by four loose ligatures around the sciatic nerve. The nerve was treated with lidocaine or saline before implementing the ligatures (silk or chromic gut). The latency of the hindlimb withdrawal to noxious mechanical and radiant heat stimuli was tested under light pentobarbital anesthesia 3-10 days following the surgery. A latency/threshold difference > or = 15% between the hindlimbs was considered to represent a change in the nocifensive response. The adapting skin temperature of the hindlimbs was also measured. Pieces of hindpaw skin and the sciatic nerve were taken for histological evaluation. The results indicate that the incidence of hyperalgesia induced by a constriction mononeuropathy depended on the noxious submodality tested, and that the thermal and mechanical hyperalgesia were not coupled in all cases. Use of only one test modality led to false negative results. Furthermore, mononeuropathy-induced changes in the adapting skin temperature produced a considerable number of false positive results (an artefactual hyperalgesia) when radiant heat alone was used to determine the nocifensive withdrawal latency without paying attention to the abnormality of the skin temperature. A preemptive lidocaine treatment of the sciatic nerve before the nerve ligation significantly reduced the incidence of mononeuropathy-induced hyperalgesia. The nerve ligation material (silk vs chromic gut) was not a significant factor for the development of hyperalgesia induced by a constriction injury of a peripheral nerve. In histological evaluation the constriction injury-induced damage of the sciatic nerve was verified, and the inflammatory reaction caused by chromic gut was not stronger than that caused by silk ligatures. In general, immunohistochemical staining for substance P decreased whereas that for VIP increased. The results support the hypothesis that ligation-induced mechanical trauma and the afferent barrage induced by it, especially during the perioperative period, plays an important role in the development of postoperative hyperalgesia.

Adaptation, Physiological↗
PubMed1996

Reduced hyperalgesia in nerve-injured WLD mice: relationship to nerve fiber phagocytosis, axonal degeneration, and regeneration in normal mice.

The pathogenesis of neuropathic pain states is influenced by inflammatory factors associated with nerve injuries and may be mediated in part by the macrophage-dependent process of Wallerian degeneration. Macrophages play a dominant role in the Wallerian (axonal) degeneration that characterizes the painful chronic constriction injury model of neuropathy by liberating proinflammatory cytokines at the site of nerve injury. These cytokines directly affect the structural integrity of neural systems and have been implicated in the development of hyperalgesic states. We hypothesized that interference with the pathologic process of Wallerian degeneration would alter the development of the neuropathic pain state. To test this hypothesis, we studied the development of thermal hyperalgesia in the chronic constriction injury model of neuropathy using normal mice and mice of the WLD strain in which recruitment of macrophages to the site of nerve injury and Wallerian degeneration are delayed. We compared the onset and magnitude of the hyperalgesia with quantitative measures of nerve injury including the phagocytic cellular activity associated with Wallerian degeneration. In C57BL/6J (6J) mice, hyperalgesia peaked 3-10 days after placement of the ligatures, qualitatively matching the response previously reported for rats. In C57BL/WLD (WLD) mice, there was reduced hyperalgesia temporally associated with reduced numbers of phagocytic cells in the injured nerve. In injured WLD nerves there was a reduced rate of axonal degeneration compared to similarly injured 6J nerves. Regeneration was correspondingly delayed in the WLD animals. The results suggest that the process of Wallerian degeneration is a key factor in the pathogenesis of hyperalgesia. Continued development of mouse models of neuropathic pain will be important in exploring the molecular basis of neuropathic pain. Interference with the cellular mediators of Wallerian degeneration may be a useful therapeutic strategy that might modulate the onset and magnitude of hyperalgesia following nerve injury.

Animals↗
PubMed2002

Effects of lornoxicam, piroxicam, and meloxicam in a model of thermal hindpaw hyperalgesia induced by formalin injection in rat tail.

Non-steroidal anti-inflammatory drugs (NSAIDs) are frequently used as analgesics. Although the results of clinical studies indicate considerable disparity in the analgesic efficacy of NSAIDs, the pre-clinical models generally used for the study of nociception do not allow a clear distinction to be made between the analgesic properties of agents belonging to this family. As clinical pain is characterized by hyperalgesia, we evaluated the effects of NSAIDs with similar chemical structures but different selectivities for cyclo-oxygenase (COX)-1 and COX-2 in a new behavioural model of central hyperalgesia in rats. We assessed the effects of lornoxicam, piroxicam, and meloxicam on the reduction of hindpaw nociceptive thresholds to thermal stimulation produced by a 10% formaldehyde (formalin) injection into rat tail. Each drug was administered intraperitoneally (i.p.) at its ED(50)for the anti-inflammatory effect (namely the inhibition of carrageenan-induced hindpaw oedema). At this dose (1.3 mg kg(-1), 1.0 mg kg(-1), and 5.8 mg kg(-1), respectively), lornoxicam, piroxicam, and meloxicam produced the same anti-inflammatory effect, did not modify thermal nociceptive thresholds, and significantly reduced the hyperalgesia. However, only lornoxicam was fully effective for prevention of hyperalgesia. Our results indicate a dissociation between the anti-inflammatory and the anti-hyperalgesic activity of NSAIDs, where the latter seems to be more evident after the block of both COX-1 and COX-2. Finally, they suggest that our experimental model of thermal hindpaw hyperalgesia can be effectively utilized to assess the ability of different drugs to reduce central sensitization, and thus hyperalgesia.

Analgesics, Non-Narcotic↗
PubMedDate not supplied

Sciatic nerve block with bupivacaine-loaded microspheres prevents hyperalgesia in an inflammatory animal model.

PURPOSE: The aim of this study was to evaluate the effect of different durations of local anesthetic neural blockade on hyperalgesia after carrageenan infiltration in a rat model. METHODS: Inflammation was obtained by injection of carrageenan in the righ hind paw. Hyperalgesia was determined by measuring the threshold of response to increasing mechanical stimuli on the contralateral and on the ipsilateral paw. The development of edema was measured. After identification of the sciatic nerve by nerve stimulation, blockade was performed either one hour before or after carrageenan infiltration. Animals were randomly assigned into three groups: without sciatic nerve block (control group; n = 20), block with bupivacaine (B) and block with bupivacaine-loaded microspheres (B-Ms) injection before or after carrageenan infiltration (n = 10 for each group). RESULTS: Carrageenan infiltration in the control group induced a severe ipsilateral and contralateral hyperalgesia. After blockade with B (duration = 2 +/- 0.5 hr) hyperalgesia was present and delayed only by the duration of the local anesthetic effect. A longer duration of block achieved with B-Ms (duration greater than five hours), was associated with the absence of development of both ipsilateral and contralateral hyperalgesia. No preemptive effect was recorded. CONCLUSION: B-Ms as a drug delivery system prolongs the duration of neural blockade and avoids hyperalgesia phenomena in this rat model of inflammation.

Anesthetics, Local↗
PubMed1997

Involvement of 5-hydroxytryptamine and bradykinin in the hyperalgesia induced in rats by collagenase from Clostridium histolyticum.

The involvement of bradykinin, 5-hydroxytryptamine, substance P and prostanoids in the hyperalgesia elicited by collagenase in rat paw was investigated. Collagenase (100 micrograms) induced a slight hyperalgesia in kininogen deficient rats in comparison with the behavioural response obtained in normal rats. Lisinopril (10(-5) M), and angiotensin-converting enzyme inhibitor, increased the duration of the hyperalgesia elicited in normal rats. Ondansetron (0.5 to 5 mumol/kg), a 5-HT3 antagonist, suppressed the hyperalgesia as did methysergide (1.1 to 11 mumol/kg), a mixed 5-HT1 and 5-HT2 receptor antagonist. However, the hyperalgesia was not modified by RP 67580 (1.8 to 18 mumol/kg), a NK1 receptor antagonist, and was only slightly delayed by indomethacin (2 mg/kg), a cyclo-oxygenase inhibitor. The oedema-promoting effect of 5-HT (6 nmol) was inhibited by methysergide but not by ondansetron. The swelling induced by collagenase in rat paw was reduced by methysergide but not by ondansetron. We conclude that the behavioural response induced by collagenase depends on an interactions between bradykinin and 5-HT. Prostanoids play a minor role in the beginning of the reaction whereas substance P is not significantly involved in this hyperalgesia.

Analgesics↗
PubMed2006

Neutrophils-derived peroxynitrite contributes to acute hyperalgesia and cell influx in zymosan arthritis.

We investigated the contribution of neutrophils to joint hyperalgesia and peroxynitrite formation in zymosan arthritis. Rats received 1 mg zymosan intra-articular, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. After 6 h, joint exudates were collected by aspiration for the assessment of cell influx, myeloperoxidase activity, and nitrite (as an index of nitric oxide formation) levels. Nitrotyrosine content, used as an index of peroxynitrite formation, was measured in joint exudates, using enzyme-linked immunosorbent assay. A group of rats was rendered neutropenic through the administration of a rabbit anti-rat neutrophil antibody (2 ml kg(-1), i.p.) 30 min before injection of 1 mg zymosan intra-articular. Other groups received uric acid (100 or 250 mg kg(-1), i.p.), the peroxynitrite scavenger, 30 min before 1 mg zymosan intra-articular. Controls received the vehicle. The significant inhibition of joint hyperalgesia in neutropenic animals was associated to significantly decreased cell influx, myeloperoxidase activity, nitric oxide, and nitrotyrosine levels in the joint exudates, as compared to naive rats. Uric acid administration inhibited both hyperalgesia and cell influx, as compared to controls. Neutrophils are involved in both nitric oxide and peroxynitrite formation in zymosan arthritis, thereby contributing to acute joint hyperalgesia. Scavenging of reactive nitrogen species (e.g. peroxynitrite) inhibits neutrophil migration and joint hyperalgesia in the acute phase of zymosan arthritis in rats.

Acute Disease↗
PubMed1995

Mechanisms of tumor necrosis factor-alpha (TNF-alpha) hyperalgesia.

Activation of immune cells by pathogens induces the release of a variety of proinflammatory cytokines, including IL-1 beta and TNF-alpha. Previous studies using IL-1 beta have demonstrated that this cytokine can alter brain function, resulting in a variety of 'illness responses' including increased sleep, decreased food intake, fever, etc. We have recently demonstrated that i.p. IL-1 beta also produces hyperalgesia and that this hyperalgesia (as well as most illness responses) is mediated via activation of subdiaphragmatic vagal afferents. The present series of studies were designed to provide an initial examination of the generality of proinflammatory cytokine-induced hyperalgesia by examining the effects of i.p. TNF-alpha on pain responsivity. These studies demonstrate that: (a) i.p. TNF-alpha produces dose-dependent hyperalgesia as measured by the tailflick test, (b) this hyperalgesia is mediated via the induced release of IL-1 beta, (c) hyperalgesia is mediated via activation of subdiaphragmatic vagal afferents, and (d) the effects of subdiaphragmatic vagotomy cannot be explained by a generalized depression of neural excitability.

Animals↗
PubMed1982

Reversal by serotonergic agents of reserpine-induced hyperalgesia in rats.

Reserpine (4 mg/kg) induced a time-dependent reduction in pain threshold (hyperalgesia) as observed by the tail-flick technique in rats. Serotonin, its precursor 5-hydroxytryptophan or the receptor agonist, quipazine reversed the reserpine-induced hyperalgesia. On the other hand, piribedil, amantadine, imipramine or desipramine treatment failed to reverse the reserpine-induced hyperalgesia. Similarly, intracerebroventricular administration of dopamine or noradrenaline also had no effect on reserpine-induced hyperalgesia. These observations not only suggested a role of serotonin in hyperalgesia but also that reserpine hyperalgesia is suitable for selective study of serotonin-mediated responses in rats.

5-Hydroxytryptophan↗
PubMed1994

The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat.

Recent studies have suggested that glia might play a more active role in synaptic function than previously thought. Therefore, the present studies have evaluated the potential role of spinal cord glia in acute nociceptive processing and in the thermal and mechanical hyperalgesia produced by peripheral injury. In the present experiments, we found that: (1) selective inhibition of glia metabolism with intrathecal (i.t.) administration of fluorocitrate (1 nmol) results in a marked, but reversible, attenuation of the persistent thermal and mechanical hyperalgesia produced by intraplantar zymosan (5 mg); (2) selective inhibition of the inducible form of nitric oxide synthase (iNOS) with i.t. aminoguanidine (1 pmol-1 nmol) resulted in a dose-dependent inhibition of the persistent thermal, but not mechanical hyperalgesia produced by intraplantar zymosan (5 mg); (3) i.t. coadministration of interleukin 1 beta (IL1 beta; 10 ng) and interferon gamma (IFN; 1000 U) resulted in expression of the message for iNOS 8 hr after administration assessed using reverse-transcription polymerase chain reaction (RT-PCR) and Southern blot analysis; and (4) i.t. administration of lipopolysaccharide (LPS; 150 micrograms) produced a time-dependent thermal hyperalgesia compared with saline treated-rats (15 microliters). There was no change in mechanical withdrawal thresholds over time following any treatment, except fluorocitrate. We have previously shown that NO plays a significant role in mechanisms of hyperalgesia. In the present experiments we have extended these observations and have now shown a role for iNOS, expressed by glia, in mechanisms of hyperalgesia. These results suggest an unexplored avenue for the development of potential new and novel therapies for pain control.

Amino Acid Oxidoreductases↗
PubMed1994

Hyperalgesia induced by Bothrops jararaca venom in rats: role of eicosanoids and platelet activating factor (PAF).

In this study we investigated the ability of Bothrops jararaca venom (BjV) to induce hyperalgesia and the modulation of this effect by lipid mediators. It was found that intraplantar injection of BjV (1 to 25 micrograms) caused a dose and time-related hyperalgesia. The peak of the hyperalgesic response was 1 hr after injection of the venom and persisted for 24 hr with the higher dose. The BjV-induced hyperalgesia was markedly attenuated by dexamethasone. Dexamethasone blocks the generation of biologically active metabolites from arachidonic acid by inhibiting PLA2 activation. Inhibition of the cyclo-oxygenase pathway by indomethacin, or inhibition of lipoxygenases by NDGA both significantly inhibited BjV-induced hyperalgesia. Two antagonists of PAF, WEB2170 and BN52021, also significantly inhibited the initial phase of the hyperalgesia. These results suggest that hyperalgesia induced by BjV is, at least partially, mediated by lipid mediators such as prostaglandins, leukotrienes and PAF.

Animals↗
PubMed1995

Peri-administration of clonidine or MK801 delays but does not prevent the development of mechanical hyperalgesia in a model of mononeuropathy in the rat.

Following loose ligation of the sciatic nerve, rats develop a persistent hyperalgesia which mimics some of the features of traumatic neuropathy seen in man. Previously, we have shown that administration of MK801 or clonidine prior to and 30 min following loose ligation of the sciatic nerve prevented the development of hyperalgesia up to 30 days following surgery. In the current study, we have extended our observation and examined the effect of administration of clonidine (1 mg/kg, s.c.) or MK801 (0.3 mg/kg, s.c.) 30 min prior to and 6 h following loose ligation of the sciatic nerve on the development of hyperalgesia assessed at 9 time points between 16 and 150 days after loose ligation. We have found that compared with saline treatment, the degree of hyperalgesia apparent in animals receiving MK801 was significantly reduced when tested 16, 28, or 42 days after surgery. No significant difference between the 2 treatment groups was detected at any other time points during the study. Similarly, when compared with saline treated controls, the degree of hyperalgesia measured in animals following peri-administration of clonidine was significantly less when measured 16 and 28 days after surgery, but did not differ significantly at any of the time points tested between 42 and 150 days following surgery. Our results indicate that peri-administration of MK801 or clonidine significantly delay, but do not prevent, the onset of neuropathic hyperalgesia.

Animals↗
PubMed1992

Sympathectomy does not abolish bradykinin-induced cutaneous hyperalgesia in man.

Bradykinin is an endogenous peptide that is thought to be a chemical mediator of the hyperalgesia following inflammation. In rat, bradykinin has been postulated to cause hyperalgesia to mechanical stimuli by releasing prostaglandin from sympathetic post-ganglionic terminals. The aim of this study was to determine whether bradykinin-induced cutaneous hyperalgesia in humans requires post-ganglionic sympathetic terminals. In humans, intradermal injection of bradykinin produces dramatic hyperalgesia to heat but not mechanical stimuli. Therefore, we measured the magnitude and duration of pain and hyperalgesia to heat stimuli following intradermal injection of bradykinin into the leg of a woman before and 6 months after an ipsilateral, surgical, lumbar sympathectomy. The pain and hyperalgesia to heat following bradykinin was found to be unaffected by the sympathectomy. These results suggest that the algesic effects of cutaneous bradykinin in human are independent of the sympathetic nervous system.

Adolescent↗
PubMed1994

Pentobarbital prevents the development of C-fiber-induced hyperalgesia in the rat.

Noxious stimuli applied to the skin can produce long-lasting, C-fiber-dependent, secondary hyperalgesia that is mediated by central mechanisms. NMDA receptor antagonists and low doses of morphine can preferentially block the development of hyperalgesia without significantly altering unpotentiated responses to nociceptive stimuli. The aim of our study was to determine if low doses of pentobarbital can also preferentially alter either hyperalgesic or unpotentiated responses to nociceptive heat stimuli in spinalized and intact rats. Our results demonstrate the following. (1) Mustard oil applied above the ankle joint or electrical stimulation of the sciatic nerve at C-fiber intensity in spinalized, unanesthetized rats decreased the latency to withdrawal of the foot from water maintained at 47-49 degrees C. This secondary hyperalgesia to thermal stimulation persisted for at least 1 h and was most likely mediated by central mechanisms. (2) Pentobarbital in both spinalized and spinal cord-intact rats prevented the development of the late component (42-120 min) but only partially decreased the early (2-6 min) component of hyperalgesia. In contrast, pentobarbital had relatively minimal effects on unpotentiated withdrawal responses. Thus, pentobarbital is similar to morphine in its ability to prevent hyperalgesia, but may differ from the anesthetic isoflurane, which does not interfere with the development of hyperalgesia.

Anesthesia↗
PubMed1994

The resolution of neuropathic hyperalgesia following motor and sensory functional recovery in sciatic axonotmetic mononeuropathies.

Nerve lesions producing extensive axonal loss can induce painful hyperalgesic states in man. The affect of axonal regeneration and end-organ reinnervation on hyperalgesia and pain is controversial. This study used two axonotmetic models, the sciatic crush injury (CI) and the sciatic chronic constrictive injury (CCI), to investigate the affects of nerve regeneration and reinnervation on hyperalgesia and presumed painful behavior in rats. The sciatic CI resulted in a transient loss of both sciatic motor function and the withdrawal response to pinch and heat in the sciatic distribution. Extensive recovery of motor function, pinch and heat response occurred over days 23-38 post-crush injury. This temporally corresponded with a plateau in the hindpaw autotomy score and a resolution of the saphenous-mediated pressure and heat hyperalgesia (adjacent neuropathic hyperalgesia; ANH) which developed over the medial dorsum of the hindpaw following the sciatic CI. In contrast, with sciatic transection and distal stump excision, no motor recovery occurs, large areas of the hindpaw remain unresponsive to heat and pinch, and the saphenous mediated ANH fails to resolve over a period of 3 months. When sciatic CI was compared to contralateral sciatic transection within the same rat, the bilateral saphenous-mediated pressure and heat thresholds were initially identical, but by 23-27 days post-crush, the crush side thresholds became hypoalgesic relative to the section side. This demonstrates an attenuation of the crush-induced ANH which temporally corresponds to the recovery of motor and sensory function. When the sciatic nerve was proximally crushed and distally transected (3 cm below the crush site), the saphenous-mediated pressure and heat threshold changes were identical (over 6 weeks of serial testing) to those produced by a contralateral sciatic transection within the same rat. This indicates that the microenvironments surrounding the regenerating axon tips did not differentially affect the development of ANH following sciatic CI or transection. The sciatic CCI resulted in a transient loss of hindpaw motor function without the loss of pinch or heat withdrawal responses in the sciatic distribution. Motor function recovery occurred primarily over days 23-59 post-ligature. During this prolonged period of motor function recovery there was a resolution of the sciatic-mediated plantar surface heat hyperalgesia and the saphenous-mediated heat ANH. The above data support the hypothesis that the successful regeneration of distal axons after axonotmetic lesions can initiate the resolution of neuropathic hyperalgesia.

Animals↗
PubMed1995

Cutaneous pretreatment with the capsaicin analog NE-21610 prevents the pain to a burn and subsequent hyperalgesia.

Cutaneous injection of the capsaicin analog NE-21610 (Procter and Gamble) produces analgesia to heat but not mechanical stimuli in humans. The present study examined whether pretreatment of the skin with NE-21610 prevents the development of hyperalgesia following heat injury. On the 1st day testing, 7 volunteers received a 30-microl intradermal injection of vehicle to one volar forearm and 10 micrograms of NE-21610 to the other volar forearm. On the 2nd test day the subjects rated the intensity of pain to mechanical and heat stimuli before and after a burn (48 degrees C, 120 sec) to each injection site. At the vehicle site, the pain evoked by the burn was rated as moderate to strong. In addition, primary hyperalgesia to heat and mechanical stimuli, secondary hyperalgesia to mechanical stimuli, and flare were observed after the burn. In contrast, the pain evoked by the burn at the NE-21610-treated site was rated as weak, and primary hyperalgesia to heat and mechanical stimuli did not develop. In addition, the area of flare at the drug-tested site was smaller than that observed at the vehicle site, and no secondary hyperalgesia to mechanical stimuli was observed. These data suggest that pretreatment with the capsaicin analog NE-21610 may attenuate the pain and hyperalgesia associated with injury.

Adult↗
PubMed1995

Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions.

Over the last several years, compelling evidence has accumulated indicating that central hyperactive states resulting from neuronal plastic changes within the spinal cord play a critical role in hyperalgesia associated with nerve injury and inflammation. Such neuronal plastic changes may involve activation of central nervous system excitatory amino acid (EAA) receptors, subsequent intracellular cascades including protein kinase C translocation and activation as well as nitric oxide production, leading to the functional modulation of receptor-ion channel complexes. Similar EAA receptor-mediated cellular and intracellular mechanisms have now been implicated in the development of tolerance to the analgesic effects of morphine, and a site of action involved in both hyperalgesia and morphine tolerance is likely to be in the superficial laminae of the spinal cord dorsal horn. These observations suggest that hyperalgesia and morphine tolerance, two seemingly unrelated phenomena, may be interrelated by common neural substrates that interact at the level of EAA receptor activation and related intracellular events. This view is supported by recent observations showing that thermal hyperalgesia develops when animals are made tolerant to morphine antinociception and that both hyperalgesia and reduction of the antinociceptive effects of morphine occur as a consequence of peripheral nerve injury. The demonstration of interrelationships between neural mechanisms underlying hyperalgesia and morphine tolerance may lead to a better understanding of the neurobiology of these two phenomena in particular and pain in general. This knowledge may also provide a scientific basis for improved pain management with opiate analgesics.

Animals↗
PubMedDate not supplied

Hyperalgesia in rats following intracerebroventricular administration of endotoxin: effect of bradykinin B1 and B2 receptor antagonist treatment.

The present study investigated the development of thermal and mechanical hyperalgesia following intracerebroventricular (i.c.v.) injections of E. coli lipopolysaccharide (LPS). Hind paw withdrawal to von Frey filament stimulation and thermal withdrawal latencies were measured before and up to 24 or 48 h following an i.c.v. injection of LPS (dose range: 0.02--200 micrograms). Thermal and mechanical hyperalgesia were evident by 6 h after LPS injection. LPS-induced hyperalgesia was reversed by the B2 receptor antagonist, HOE 140 (10--30 pmol), when administered i.c.v. but not systemically (0.01--1 mmol/kg, i.v.). Central co-administration of the B1 receptor antagonists, des-Arg9-Leu8 Bk (0.1--1 nmol) or des-Arg10 HOE 140 (0.1--1 nmol) had no effect on thermal or mechanical hyperalgesia. LPS-induced hyperalgesia was also inhibited by indomethacin administered either i.c.v. (10 nmol) or i.v. (1 mumol/kg). These results indicate that administration of endotoxin to the CNS induces the development of hyperalgesia and that this response involves the activity of kinins, via the stimulation of centrally located B2 receptors, and the formation of prostanoids.

Analysis of Variance↗
PubMed1996

Delayed sympathectomy after a prolonged hyperalgesia results in a subsequent enhanced acute hyperalgesic response.

We report on the ability of a delayed sympathectomy after a prolonged hyperalgesia to result in a subsequent enhanced hyperalgesic response. Sympathectomy was performed one day after injection of prostaglandin E2 plus rolipram, which induces a prolonged sympathetically-maintained hyperalgesia [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. The duration of hyperalgesia produced by a subsequent injection of prostaglandin E2 or prostaglandin E2 plus rolipram was then assessed. Lumbar surgical sympathectomy, done on day 2 or 3, prevented prostaglandin E2 plus rolipram-induced prolonged hyperalgesia from developing when they were injected five days after surgery, similar to the previous report of the effect of prior sympathectomy to block the rolipram enhancement [Aley K. O. and Levine J. D. (1995) Eur. J. Pharmac. 273, 107-112]. Sympathectomy done five days after injection of prostaglandin E2 plus rolipram, however, paradoxically prolonged (at least 10 days) hyperalgesia induced by a subsequent prostaglandin E2 plus rolipram injection, a duration much greater than that seen after prostaglandin E2 plus rolipram in naive animals. To determine the roles of prostaglandin E2 and rolipram in the prolongation of hyperalgesic response after delayed sympathectomy, rats were treated with either prostaglandin E2 or rolipram prior to sympathectomy. Prostaglandin E2 or rolipram alone were also administered five days after the sympathectomy. It was found that sympathectomy done five days after first injecting either prostaglandin E2 or rolipram alone did not produce enhanced hyperalgesic response. These data suggest that induction of a prolonged state of mechanical hyperalgesia causes time-dependent alterations in the sympathetic control of peripheral nociceptive mechanisms such that sympathectomy can lead to enhanced hyperalgesic response. These findings may be relevant to post-sympathectomy pain, a clinical entity for which there has been no available animal models.

Animals↗