Spinal N-acetyl-alpha-linked acidic dipeptidase (NAALADase) inhibition attenuates mechanical allodynia induced by paw carrageenan injection in the rat.

N-Acetylated-alpha-linked acidic dipeptidase (NAALADase) hydrolyzes N-acetyl-aspartyl-glutamate (NAAG) to liberate N-acetyl-aspartate and glutamate. NAAG is a putative neurotransmitter and acts as a mixed agonist/antagonist on N-methyl-D-aspartate (NMDA) receptors and acts as an agonist on the metabotropic glutamate receptor 3 (mGluR3). In the present study, we examined the role of spinal NAALADase in the maintenance of mechanical allodynia induced by carrageenan injection, skin incision and mild thermal injury using 2-(phosphonomethyl)pentanedioic acid (2-PMPA), a specific NAALADase inhibitor, in rats. Mechanical allodynia was induced by injection of 2 mg carrageenan into the paw (carrageenan model), by creating a 1-cm longitudinal skin incision of the plantar aspect of the foot (post-operative model), or by application of thermal stimulation (52.5 degrees C) for 45 s to the hind paw (mild thermal injury model). 2-PMPA was administered intrathecally at the time when the maximum mechanical allodynia occurred. Mechanical allodynia was assessed by the measurement of mechanical threshold using von Frey filaments. The mechanical threshold was measured 5, 15, 30, 60 and 90 min after the drug administration. In the carrageenan model, 100 microg of 2-PMPA attenuated the level of mechanical allodynia. 2-PMPA had no effect on the level of mechanical allodynia in both the post-operative pain model and the mild thermal injury model. These data suggested that the inhibition of spinal NAALADase alleviated mechanical allodynia induced by paw carrageenan injection.

Antagonism of ORLI receptor produces an algesic effect in the rat formalin test.

The authors investigated the role of endogenously released nociceptin (also known as orphanin FQ) spinal and supraspinal nociceptive transmission during the rat formalin test by examining the effect of intrathecal and intracerebroventricular injection of J-113397, a non-peptidyl ORL1 receptor selective antagonist. When J-113397 was injected intrathecally or intracerebroventricularly 10 min before the formalin injection, it enhanced the agitation behavior induced by paw formalin injection. This suggested that paw formalin injection induced nociceptin release in the spinal cord and the supraspinal brain sites, that this endogenously released nociceptin produced an analgesic effect and that J-113397 antagonized this analgesic effect of nociceptin and produced an algesic effect in the rat formalin test.

Inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect in the rat formalin test.

N-acetyl-aspartyl-glutamate is a putative neurotransmitter and acts as a weak agonist at the N-methyl-D-aspartate receptor. N-acetyl-aspartyl-glutamate also acts as an agonist at the metabotropic glutamate receptor 3. N-acetyl-aspartyl-glutamate is hydrolyzed by N-acetylated-alpha-linked acidic dipeptidase to liberate N-acetyl-aspartate and glutamate. Recently, a specific inhibitor of N-acetylated-alpha-linked acidic dipeptidase, 2-(phosphonomethyl)pentanedioic acid, has been reported. In the present study, we examined the effect of i.t. administered 2-(phosphonomethyl)pentanedioic acid in the rat formalin test (a model of inflammatory pain) and the rat hot plate test. In the formalin test, drugs were administered 10min before (pre-treatment study) or 7min after (post-treatment study) the formalin injection. The paw formalin injection induces biphasic flinching (phase 1: 0-2min; phase 2: 10-60min) of the injected paw. In the pre-treatment study, i.t. administered 2-(phosphonomethyl)pentanedioic acid depressed both phases 1 and 2 flinching behavior in a dose-dependent manner but 2-(phosphonomethyl)pentanedioic acid had no effect on the flinching behavior in the post-treatment study. In the pre-treatment study, the potency of 2-(phosphonomethyl)pentanedioic acid in depressing the phase 2 response is greater than that in depressing the phase 1 response. Intrathecal injection of 2-(phosphonomethyl)pentanedioic acid had no effect in the hot plate test. We suggest that N-acetylated-alpha-linked acidic dipeptidase plays an important role in spinal nociceptive transmission and that inhibition of spinal N-acetylated-alpha-linked acidic dipeptidase produces an antinociceptive effect during the rat formalin test but not during the hot plate test.

Usefulness of the evidence-based medicine-supported cancer pain management guideline.

The Japanese guidelines for the clinical practice of cancer pain management supported by evidence-based medicine were established by the Japanese Society for Palliative Medicine in 1999 [as their Evidence-based Medicine-supported Cancer Pain Management Guideline ]. To evaluate usefulness of the Guideline for the management of cancer pain, the same questionnaires were addressed to nurses and physicians of enrolled institutions twice. The first survey was conducted before the distribution of the Guideline in July, 1999 and the second was done after the distribution in January, 2000. Usefulness of the Guideline was examined by comparing the results of two surveys. Cancer patients were divided into two groups depending on their stages (conservative or terminal). (1) Morbidity of pain in cancer patients at each stage having some analgesics did not change at each survey period. (2) At the first survey the rate of pain relief in each stage of cancer patients was essentially unchanged from a previous result obtained in 1998. (3) The rate of pain relief shown in the second survey tended to be higher than that shown in the first in both groups of patients. (4) The rate of pain relief with per os morphine was shown to be significantly higher in the second survey than in the first for each group of patients at conservative or terminal stage. (5) The rate of pain relief of patients staying in the ward where the guidance for dosing of morphine had been carried out was 37.5% at the first survey versus 47.9% at the second. (6) The answers from physicians to questions about treatment of cancer pain remained unchanged between the first and the second survey. The usefulness of the Guideline for cancer pain management is partly confirmed by these results. The significance of the Guideline will be totally discussed by comparing its effects on nurses, pharmacists and physicians.

Anti-allodynic effects of oral COX-2 selective inhibitor on postoperative pain in the rat.

PURPOSE: To examine the effect of a cyclooxygenase (COX)-2 inhibitor on the maintenance of mechanical allodynia induced by skin incision (an animal model of postoperative incident pain) in the rat. Also, to compare the effect of a COX-2 inhibitor with that of a nonselective COX-1 and COX-2 inhibitor and B2 receptor antagonist. METHODS: A 1 cm longitudinal skin incision was made in the plantar aspect of the foot. JTE522 (1-100 mg x kg(-1)), a COX-2 inhibitor, indomethacin (1-30 mg x kg(-1)), a nonselective COX-1 and COX-2 inhibitor, or FR173657 (10 and 100 mg x kg(-1)), a bradykinin B2 receptor antagonist, was administered orally five minutes after the end of the surgery. The level of mechanical allodynia was assessed by measuring the frequency of foot withdrawal in response to the application of a 12.5 g on Frey filament at 2, 4, 6, 8 and 24 hr after the drug administration. RESULTS: Oral administration of JTE522 or indomethacin attenuated the maximum response frequency in a dose-dependent manner at a dose between 1 and 30 mg x kg(-1) (P < 0.05). Oral FR 173657, (100 mg x kg(-1)), had no effect on the maximum response frequency. CONCLUSION: These data indicated that a COX-2 inhibitor attenuated the level of mechanical allodynia in the rat model of postoperative pain.

The spinal biology in humans and animals of pain states generated by persistent small afferent input.

Behavioral models indicate that persistent small afferent input, as generated by tissue injury, results in a hyperalgesia at the site of injury and a tactile allodynia in areas adjacent to the injury site. Hyperalgesia reflects a sensitization of the peripheral terminal and a central facilitation evoked by the persistent small afferent input. The allodynia reflects a central sensitization. The spinal pharmacology of these pain states has been defined in the unanesthetized rat prepared with spinal catheters for injection and dialysis. After tissue injury, excitatory transmitters (e.g., glutamate and substance P) acting though N-methyl-D-aspartate (NMDA) and neurokinin 1 receptors initiate a cascade that evokes release of (i) NO, (ii) cyclooxygenase products, and (iii) activation of several kinases. Spinal dialysis show amino acid and prostanoid release after cutaneous injury. Spinal neurokinin 1, NMDA, and non-NMDA receptors enhance spinal prostaglandin E2 release. Spinal prostaglandins facilitate release of spinal amino acids and peptides. Activation by intrathecal injection of receptors on spinal C fiber terminals (mu,/delta opiate, alpha2 adrenergic, neuropeptide Y) prevents release of primary afferent peptides and spinal amino acids and blocks acute and facilitated pain states. Conversely, consistent with their role in facilitated processing, NMDA, cyclooxygenase 2, and NO synthase inhibitors act to diminish only hyperalgesia. Importantly, spinal delivery of several of these agents diminishes human injury pain states. This efficacy emphasizes (i) the role of facilitated states in humans, (ii) shows the importance of spinal systems in human pain processing, and (iii) indicates that these preclinical mechanisms reflect processes that regulate the human pain experience.

Nociceptin/orphanin FQ: role in nociceptive information processing.

Recently, opioid receptor like1 (ORL1) receptor was identified. The ORL1 receptor is a G protein coupled receptor and the sequence of the ORL1 receptor is closely related to that of the opioid receptors. Nociceptin/orphanin FQ has been identified as a potent endogenous agonist of the ORL1 receptor and the sequence of nociceptin/orphanin FQ is closely related to that of dynorphin A. Nociceptin/orphanin FQis not active at the classical opioid receptors, such as mu, kappa and delta receptors. The distribution of prepronociceptin mRNA is distinct from that of the opioid peptide precursor. Mice lacking the ORL1 receptor showed no significant differences in nociceptive threshold compared with wild mice. The role of nociceptin/orphanin FQ on nociceptive transmission is unclear. Intracerebroventricular (i.c.v.) injection of nociceptin/orphanin FQ produced hyperalgesia and allodynia and antagonized morphine analgesia. On the other hand, intrathecal injection of low dose nociceptin/orphanin FQ produces allodynia, but high dose of nociceptin/orphanin FQ produces an analgesic effect. Although we do not fully understand the mechanisms that produce the difference between the effect of i.c.v. injection of nociceptin/orphanin FQ and that of intrathecal injection of nociceptin/orphanin FQ, we believe that spinal ORL1 receptor may be the next receptor which should be targeted by drugs designed for the treatment of pain.

Characterization of the antihyperalgesic action of a novel peripheral mu-opioid receptor agonist--loperamide.

BACKGROUND: Preclinical and clinical evidence indicates that locally administered opioid agonists produce an antihyperalgesic effect through peripheral opioid receptors in inflamed tissue. Loperamide, a mu opioid agonist, does not cross the blood-brain barrier and therefore lacks central effects after systemic administration. The authors defined the effects of topical loperamide on a thermal injury-induced hyperalgesia. METHODS: In halothane-anesthetized rats, thermal injury was induced by placing the plantar surface of a hindpaw on a hot plate (52.0+/-1 degrees C) for 45 s. Loperamide was prepared in a cream emulsion (ADL 2-1294B, 0.5%, 1.7%, and 5.0%). The drug was applied as follows: before or after injury on the injured paw and on a normal paw and after injury on the injured paw of morphine-tolerant rats. Paw withdrawal latency to a radiant heat source was measured to determine the nociceptive threshold. A pharmacokinetic study was performed with the use of 14C-labeled drug. RESULTS: Thermal injury yielded a significant thermal hyperalgesia. Loperamide, but not the vehicle, posttreatment on the injured paw resulted in a dose-dependent antihyperalgesic effect, which was reversible with naloxone (1 mg/kg given intraperitoneally). Treatment with loperamide on the normal paw produced short-lasting hypoalgesia, but the effect was not reversible with naloxone. Pretreatment at 1 and 2 but not 4 h with loperamide was effective. A rightward shift of the dose-response curve was observed in rats made tolerant to systemic morphine with subcutaneous morphine pellets. No rats with drug treatment displayed any evident behavior changes (eg., loss of corneal or pinna reflexes or change in ambulation). Drug activity in the tissue revealed an elimination half life of 2.3 h and negligible concentration in the blood. CONCLUSIONS: Loperamide, a peripherally acting mu opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.

A novel model of primary and secondary hyperalgesia after mild thermal injury in the rat.

Secondary hyperesthesia was investigated in a rat thermal injury model. After a mild focal thermal injury (52 degrees C/45 s) to the rat heel, the response latency for a thermal stimulus directed at the injured site was reduced (10 --> 6 s; e.g. primary thermal hyperalgesia) but no change was seen at the distal site. Conversely, tactile threshold at the distal site was significantly reduced (15 --> 5 g; e.g. secondary tactile allodynia) but much less so at the injured site. Magnitude of the secondary tactile allodynia paralleled the severity of the primary injury. Accordingly, this model has the same characteristics seen in human post-tissue-injury hyperesthetic states and provides a tool for the study of mechanisms underlying primary and secondary hyperesthesia.

Involvement of nitric oxide in peripheral antinociception mediated by kappa- and delta-opioid receptors.

UNLABELLED: Nitric oxide (NO) has been reported to enhance the analgesic effect of the peripherally administered mu-opioid receptor agonists, but the role of NO on the analgesic effect of the peripherally administered kappa and delta opioid receptor agonists is still unclear. We examined the effects of peripherally applied kappa- and delta-opioid receptor agonists and of their interactions with the NO-releasing drug, FK409, on the behavioral response to intraplantar injection of formalin in rats (the formalin test). The formalin injection results in a biphasic appearance of agitation behavior, consisting of the early (Phase 1; 0-9 min) and late (Phase 2; 10-60 min) responses. The active enantiomer of kappa-opioid receptor agonist, (-)U50,488H, dose-dependently suppressed the agitation response in both phases of the formalin test when applied peripherally. A peripheral delta-opioid receptor agonist, [D-Pen(2,5)] enkephalin (DPDPE), suppressed only Phase 2 of the formalin test. Local application of FK409 after the administration of a subthreshold dose of each opioid resulted in a dose-dependent decrease in the Phase 1, but not Phase 2, response to the formalin test for both agonists. Interactions between peripheral opioids and FK409 were reversed with both naloxone and carboxy-PTIO (NO scavenger). Systemic injections of either a kappa- or delta-agonist had no interaction with peripherally applied FK409. Peripheral FK409 alone did not have any significant effect on the formalin test. These data indicate that the antinociceptive effects of peripherally applied kappa- and delta-opioid agonists on the formalin test are potentiated by the local action of NO. IMPLICATIONS: The analgesic effects of peripherally applied kappa- and delta-opioid receptor agonists during inflammation induced by formalin injection in the rat are, at least partly, mediated by the NO-cGMP pathway.

The interaction of FK409, a novel nitric oxide releaser, and peripherally administered morphine during experimental inflammation.

UNLABELLED: Nitric oxide (NO) may play an important role in central and peripheral nociceptive processes. However, its contribution to peripheral antinociception is still not clear. In the present study, we investigated the effect of peripherally administered FK409, a spontaneous NO releaser, and its interaction with peripheral morphine analgesia during the rat formalin test. Intraplantar injection of formalin resulted in a biphasic appearance of flinching behavior (Phase 1 = 0-9 min, Phase 2 = 10-60 min). First, an intraplantar injection of FK409 was given 5 min before the formalin injection to test for its effect alone. In the next experiment, morphine was administered first, followed 15 min later by the phosphate buffer (pH 6.0) or FK409 injection, and 5 min later by the formalin injection. FK409 alone had no effect on the number of flinches in either phase. However, when administered after intraplantar morphine, FK409 dose-dependently depressed the agitation behavior in both phases. It shifted the dose-response curve of morphine to the left. Naloxone and carboxy-PTIO (an NO scavenger) each reversed the suppressant effect of morphine and FK409 given together. These data suggest that NO enhances the analgesic effect of peripherally administered morphine in the formalin test. IMPLICATIONS: Peripherally administered nitric oxide itself has no analgesic effect, but it enhances the analgesic effects of peripherally administered morphine during inflammation induced by paw formalin injection in the rat.

Effects of intrathecally administered nociceptin, an opioid receptor-like1 receptor agonist, and N-methyl-D-aspartate receptor antagonists on the thermal hyperalgesia induced by partial sciatic nerve injury in the rat.

BACKGROUND: Nociceptin is a 17-amino acid peptide and acts as a potent endogenous agonist of the opioid receptor-like1 receptor. Nociceptin is reported to depress glutamatergic transmission and to block the spinal facilitation that is thought to be mediated by the N-methyl-D-aspartate (NMDA) receptor. In the present study, the authors investigated the effect of intrathecally administered nociceptin and NMDA antagonists on the level of thermal hyperalgesia after partial sciatic nerve injury in the rat. METHODS: Partial sciatic nerve injury was created by tight ligation of one third to one half of the right sciatic nerve. The level of thermal hyperalgesia was evaluated by the difference score, which was calculated by subtracting the paw withdrawal latency against thermal nociceptive stimulation in the uninjured paw from that in the injured paw. Drugs were administered intrathecally 7 or 11 days after the nerve injury, and the level of thermal hyperalgesia was measured 5, 15, 30, 60, and 90 min after the drug injection. RESULTS: Intrathecal injection of nociceptin, but not of NMDA antagonists, attenuated the level of thermal hyperalgesia in a dose-dependent manner at a dose of 0.17-17 nM (post-drug difference score: saline-treated rats, -4.9 +/- 2.2 s; 17 nM nociceptin-treated rats, -1.3 +/- 0.9 s). CONCLUSIONS: Intrathecal injection of nociceptin attenuated the level of thermal hyperalgesia induced by partial sciatic nerve injury, and NMDA receptor-dependent spinal facilitation does not play an important role in maintaining thermal hyperalgesia in rats with partial sciatic nerve injury.

Analgesic effect of intrathecally administered nociceptin, an opioid receptor-like1 receptor agonist, in the rat formalin test.

Nociceptin (a heptadecapeptide also known as orphanin FQ) is a potent endogenous agonist of the opioid receptor-like1 receptor and has a sequence similar to dynorphin A. It has been reported that intracerebroventricularly injected nociceptin produced hyperalgesia in mice and that intrathecal injection of nociceptin inhibits the spinal sensitization. In the present study, we investigated the effect of intrathecally administered nociceptin in the rat formalin test (a model of inflammatory pain) and the rat hot plate test. In the formalin test, drugs were administered 10 min before (pre-treatment study) or 7 min after (post-treatment study) the formalin injection. The paw formalin injection induces a biphasic flinching (phase 1, 0-7 min; phase 2, 10-60 min) of the injected paw. In the pre-treatment study, intrathecally administered nociceptin depressed both the phase 1 and phase 2 flinching behaviour in a dose-dependent manner, and, in the post-treatment study, intrathecal injection of nociceptin depressed the phase 2 flinching behaviour. In the pre-treatment study, the potency of nociceptin in depressing the phase 1 response was the same as that in depressing the phase 2 response. These effects of nociceptin were not antagonized by the co-administration of naloxone. Intrathecal injection of nociceptin had no effect on the hot plate test. These data suggest that nociceptin plays an important role in spinal nociceptive transmission through the activation of a naloxone-insensitive receptor, and spinally administered nociceptin produces an analgesic effect during the rat formalin test, but not the hot plate test.

Role of spinal cyclooxygenase (COX)-2 on thermal hyperalgesia evoked by carageenan injection in the rat.

Prostaglandins, which are known to play an important role in the nociceptive transmission in the spinal cord, are produced by cyclooxygenase (COX). Two forms of COX have been identified, COX-1 (constitutive form) and COX-2 (a form highly inducible in response to inflammatory stimuli). COX-2 mRNA was reported to be expressed in the brain in normal rats in the absence of inflammation. We investigated the role of spinal COX-2 in the maintenance of thermal hyperalgesia induced by paw carageenan injection in the rat using NS-398, a selective COX-2 inhibitor. Intrathecally administered NS-398 attenuated the level of thermal hyperalgesia in a dose-dependent manner. This suggested that spinal COX-2 plays an important role in the maintenance of thermal hyperalgesia induced by paw carageenan injection.

Effects of intrathecally administered nociceptin, an opioid receptor-like1 (ORL1) receptor agonist, on the thermal hyperalgesia induced by carageenan injection into the rat paw.

Nociceptin is a 17 amino acid peptide and acts as a potent endogenous agonist of the opioid receptor-like1 (ORL1) receptor. Nociceptin is reported to depress glutamatergic transmission and to block the spinal facilitation which is thought to be mediated by the activation of N-methyl-D-aspartate (NMDA) receptor. Paw carageenan injection induces thermal hyperalgesia which has been reported to be maintained by the NMDA receptor dependent spinal facilitation. In the present study, we investigated the effect of intrathecally administered nociceptin on the level of thermal hyperalgesia induced by carageenan injection in the rat. Nociceptin depresses the level of thermal hyperalgesia in a dose-dependent manner. These data suggest that spinal ORL1 receptor activation depresses the spinal facilitation state induced by paw carageenan injection.

Effects of intrathecally administered nociceptin, an opioid receptor-like1 (ORL1) receptor agonist, on the thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat.

Nociceptin is a 17 amino acid peptide which acts as a potent endogenous agonist of the opioid receptor-like1 (ORL1) receptor. In the spinal cord, nociceptin is reported to depress glutamatergic transmission and to block the spinally mediated facilitation which is thought to be mediated by the activation of N-methyl-D-aspartate (NMDA) receptor. It has been found that NMDA receptor mediated spinal facilitation is crucial in the maintenance of thermal hyperalgesia evoked by a nerve constriction injury. In the present study, we investigated the effect of intrathecally administered nociceptin on the level of thermal hyperalgesia after unilateral constriction injury to the sciatic nerve in the rat. Intrathecally administered nociceptin attenuated the level of thermal hyperalgesia in a dose dependent manner. These data indicate that spinal ORL1 receptor activation by nociceptin inhibits the spinal facilitation evoked by the nerve constriction injury.

Analysis of the effects of cyclooxygenase (COX)-1 and COX-2 in spinal nociceptive transmission using indomethacin, a non-selective COX inhibitor, and NS-398, a COX-2 selective inhibitor.

Prostaglandins are now thought to play an important role in nociceptive information transmission in the spinal cord. Prostaglandins are known to be produced by cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid. Two forms of COX have been identified: COX-1, which is constitutively expressed in most tissues and organs, and COX-2, which is an inducible enzyme and is localized primarily in inflammatory cells and tissues. COX-2 mRNA has been reported to be expressed in the brain in normal rats. We investigated the role of COX-1 and COX-2 in the spinal nociceptive transmission during the rat formalin test and the hot plate test using indomethacin, a non-selective COX-1 and COX-2 inhibitor, and NS398, a selective COX-2 inhibitor. In the formalin test, drugs were administered intrathecally or intraperitoneally 10 min before (pre-treatment study) or 7 min after (post-treatment study) the formalin injection. Both intrathecally administered indomethacin and NS398 inhibited the formalin induced flinching behavior in a dose-dependent manner in the pre-treatment study, but not in the post-treatment study. Both indomethacin and NS398 had no effect on the hot plate test at a dose which depressed the formalin induced flinching behavior. These data suggested that COX-2 is expressed in the central nervous system, including the spinal cord, and that COX-2 plays an important role in the spinal nociceptive transmission during the formalin test, but not during the hot plate test.

Clonidine, but not morphine, delays the development of thermal hyperesthesia induced by sciatic nerve constriction injury in the rat.

BACKGROUND: It has been shown that the spinal facilitation induced by the injury discharge evoked by a nerve constriction injury is crucial in the development of thermal hyperesthesia. Both opioids and alpha 2 agonists have been reported to prevent the development of spinal facilitation evoked by the small afferent input to the spinal cord. Moreover, it has been reported that the thermal hyperesthesia induced by a nerve constriction injury is sympathetically maintained and that spinally administered alpha 2 agonists can modulate the sympathetic outflow from the spinal cord. The current study investigated the effect of spinally administered morphine and clonidine, an alpha 2 agonist, on the development of thermal hyperesthesia induced by nerve constriction injury in the rat. METHODS: A model of thermal hyperesthesia induced by a constriction injury created by making four loose ligatures around the rat sciatic nerve was used to examine the development of thermal hyperesthesia. Morphine, clonidine, and idazoxan were administered intrathecally or intraperitoneally 20 min before (pretreatment study) or 20 min after (posttreatment study) the nerve injury. RESULTS: Pretreatment, but not posttreatment, with intrathecal clonidine significantly delayed the development of thermal hyperesthesia in a dose-dependent manner, and this delay in onset produced by clonidine was 3 days after the nerve injury. This effect of clonidine's was completely antagonized by the coadministration of idazoxan with clonidine. Intrathecal morphine had no effect on the development of thermal hyperesthesia in this study. CONCLUSIONS: Spinal alpha 2 receptors, but not opioid receptors, may play an important role in the development of thermal hyperesthesia induced by a nerve constriction injury. This suggested that the activation of spinal alpha 2 receptor may reduce the sympathetic outflow and this reduction of sympathetic outflow may be the key mechanism that delays the development of thermal hyperesthesia.

The effects of intrathecally administered FK480, a cholecystokinin-A receptor antagonist, and YM022, a cholecystokinin-B receptor antagonist, on the formalin test in the rat.

Cholecystokinin (CCK) is located in the brain and the spinal cord, and CCK antagonist is reported to enhance the analgesic effect of morphine. It has been suggested that, during inflammation, the level of endogenous opioid peptides increases in the spinal cord. Intrathecally administered CCK antagonist may have some analgesic effect during inflammation via the activated spinal opioid system. To gain a better understanding of the roles of CCK-A and CCK-B receptors in spinal nociceptive transmission during inflammation, this study evaluated the effects of intrathecally administered FK480 (a CCK-A receptor antagonist) and YM022 (a CCK-B receptor antagonist). Inflammation was induced by paw formalin injection (formalin test) in rats. The subcutaneous injection of formalin into the hind paw evoked biphasic flinching (Phase 1, 0-9 min; Phase 2, 10-60 min) of the injected paw. Drugs were administered intrathecally 10 min before (pretreatment) or 7 min after (posttreatment) the formalin injection. Neither pretreatment nor posttreatment with FK480 has any effect on the formalin test. Pretreatment, but not posttreatment, with YM022 depressed the Phase 1 and Phase 2 flinching behavior in a dose-dependent manner, and this YM022 effect was stereospecific and was not antagonized by naloxone. These data indicate that a CCK-B receptor antagonist, but not a CCK-A receptor antagonist, produces an antinociceptive effect in the rat formalin test. This effect of a CCK-B receptor antagonist was not mediated by the spinal opioid receptor activation.

Role of cholecystokinin-B receptor in the maintenance of thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat.

To gain a better understanding of the role of cholecystokinin (CCK)-B receptor in the maintenance of thermal hyperalgesia induced by unilateral constriction injury to the sciatic nerve in the rat, this study evaluated the effects of intrathecally administered YM022 (a CCK-B receptor antagonist) on thermal hyperalgesia. Drugs were administered intrathecally 1 or 5 weeks after the nerve injury (1 and 5 week study). In the 5 week study, but not the 1 week study, YM022 attenuated the level of thermal hyperalgesia in a dose-dependent manner. These data indicate that a CCK-B receptor antagonist attenuates the level of thermal hyperalgesia and this effect of a CCK-B receptor antagonist is time-dependent.