Roles of opioid receptor subtypes on the antinociceptive effect of intrathecal sildenafil in the formalin test of rats

Recently, it has been known that the antinociception of sildenafil, a phosphodiesterase 5 inhibitor, is mediated through the opioid receptors. There are common three types of opioid receptors mu, delta, and kappa. We characterized the role of subtypes of opioid receptor for the antinociception of sildenafil at the spinal level. Intrathecal catheters were placed for drug delivery and formalin solution (5%, 50 microl) was injected for induction of nociception within male SD rats. The effect of mu opioid receptor antagonist (CTOP), delta opioid receptor antagonist (naltrindole), and kappa opioid receptor antagonist (GNTI) on the activity of sildenafil was examined. Intrathecal sildenafil decreased the flinching responses during phases 1 and 2 in the formalin test. Intrathecal CTOP and naltrindole reversed the antinociception of sildenafil during both phases in the formalin test. Intrathecal GNTI reversed the effect of sildenafil during phase 2, but not phase 1. These results suggest that sildenafil is effective to acute pain and the facilitated pain state at the spinal level. Both mu and delta opioid receptors are involved. However, it seems that kappa opioid receptors play in the effect of sildenafil.     

Roles of adenosine receptor subtypes on the antinociceptive effect of sildenafil in rat spinal cord

We recently found that the antinociceptive effects produced by intrathecal administration of sildenafil, a phosphodiesterase 5 inhibitor, were reversed by a nonspecific adenosine receptor antagonist, suggesting that adenosine receptors are involved in sildenafil-induced antinociception. Four adenosine receptor subtypes have been identified: A₁, A_2A, A_2B, and A₃. We examined the involvement of spinal adenosine receptor subtypes in the antinociceptive effects of intrathecal sildenafil. Intrathecal catheters were implanted in male SD rats, and nociception was assessed using the formalin test, which consisted of a subcutaneous injection of 50 μl of 5% formalin solution into the hind paw. We examined the effects of an adenosine A₁ receptor antagonist (CPT), an adenosine A_2A receptor antagonist (CSC), an adenosine A_2B receptor antagonist (alloxazine), and an adenosine A₃ receptor antagonist (MRS 1220) on sildenafil-induced antinociception. Intrathecal sildenafil suppressed formalin-induced flinching during phases 1 and 2 of the test in a dose-dependent manner. Intrathecal CPT, CSC, alloxazine, and MRS 1220 all suppressed the antinociceptive effects of sildenafil during both phases of the formalin test. These results suggest that sildenafil is an effective treatment for acute pain and the facilitated pain state at the spinal level. Additionally, spinal adenosine A₁, A_2A, A_2B, and A₃ receptors may play a role in sildenafil-induced antinociception.     

The anatomical characteristics of the stria terminalis in the human brain: a diffusion tensor tractography study

The role played by spinal adrenergic and cholinergic receptors in the antinociceptive effects of intrathecal sildenafil in formalin-induced nociception was examined. Intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats, and nociception was assessed using the formalin test, consisting of a subcutaneous injection of 50 μL of 5% formalin solution into the hind paw. We examined the effects of an alpha 1 adrenergic receptor antagonist (prazosin), an alpha 2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) on sildenafil-induced antinociception. Intrathecal sildenafil (3, 10, and 30 μg) suppressed, in a dose-dependent manner, formalin-induced flinching during phases 1 and 2 of the test. Intrathecal sildenafil (30 μg) could not show any effects against intrathecal prazosin (3 μg), yohimbine (10 μg), atropine (10 μg), and mecamylamine (10 μg) pretreatment during both phases of the formalin test. These results suggest that intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Additionally, spinal alpha 1, alpha 2, muscarinic and nicotinic receptors might play a role in sildenafil-induced antinociception.     

Receptors involved in the antinociception of intrathecal melatonin in formalin test of rats

The authors examined the antinocicepotive effect of melatonin in a nociceptive state and investigated a possible interaction with adrenergic or cholinergic receptors underlying this effect at the spinal level. Nociception was induced by a subcutaneous injection of 50 μl of a 5% formalin solution to the hindpaw of male Sprague–Dawley rats. The reversal effects of alpha-1 adrenoceptor antagonist (prazosin), alpha-2 adrenoceptor antagonist (yohimbine), muscarinic receptor antagonist (atropine) and nicotinic receptor antagonist (mecamylamine) on the activity of melatonin were assessed. Intrathecal melatonin reduced the flinching response during phase 1 and phase 2 in the formalin test. Intrathecal prazosin, yohimbine, atropine and mecamylamine increased the attenuating flinching response in both phases observed by intrathecal melatonin. Collectively, the present data suggest that intrathecal melatonin attenuates the facilitated state and acute pain evoked by formalin injection. Furthermore, the antinociception of melatonin is mediated through the alpha-1 adrenoceptor, alpha-2 adrenoceptor, muscarinic and nicotinic receptors in the spinal cord.     

Spinal gabapentin and antinociception: mechanisms of action

Spinal gabapentin has been known to show the antinociceptive effect. Although several assumptions have been suggested, mechanisms of action of gabapentin have not been clearly established. The present study was undertaken to examine the action mechanisms of gabapentin at the spinal level. Male SD rats were prepared for intrathecal catheterization. The effect of gabapentin was assessed in the formalin test. After pretreatment with many classes of drugs, changes of effect of gabapentin were examined. General behaviors were also observed. Intrathecal gabapentin produced a suppression of the phase 2 flinching, but not phase 1 in the formalin test. The antinociceptive action of intrathecal gabapentin was reversed by intrathecal NMDA, AMPA, D-serine, CGS 15943, atropine, and naloxone. No antagonism was seen following administration of bicuculline, saclofen, prazosin, yohimbine, mecamylamine, L-leucine, dihydroergocristine, or thapsigargin. Taken together, intrathecal gabapentin attenuated only the facilitated state. At the spinal level, NMDA receptor, AMPA receptor, nonstrychnine site of NMDA receptor, adenosine receptor, muscarinic receptor, and opioid receptor may be involved in the antinociception of gabapentin, but GABA receptor, L-amino acid transporter, adrenergic receptor, nicotinic receptor, serotonin receptor, or calcium may not be involved.     

Spinal antinociceptive action of loperamide is mediated by opioid receptors in the formalin test in rats

Opioids like morphine produce antinociception after intrathecal administration. Being hydrophilic in nature, morphine also spreads rostrally which leads to respiratory depression. Loperamide has been reported to produce antinociception after both intracisternal and intrathecal administration. It is also hydrophobic, which could restrict its diffusion in the spinal canal. However, the mechanism of its antinociceptive action after intrathecal administration is not definitely known. In the present study, the antinociceptive effect of loperamide was evaluated by the formalin test. It significantly inhibited Phase II flinching behavior. This antinociceptive effect was reversed by pre-administration of naloxone indicating that it was predominantly due to activation of opioid receptors.     

Roles of adenosine and serotonin receptors on the antinociception of sildenafil in the spinal cord of rats

Purpose

The phosphodiesterase 5 inhibitor sildenafil has antinociceptive effects, mediated by an increase in cGMP. This study examined the role of spinal adenosine and serotonin receptors played in the antinociceptive effects of intrathecal sildenafil.

Materials and Methods

Intrathecal catheters were inserted into the subarachnoid space of Sprague-Dawley male rats as a drug delivery device. Pain was induced by injecting formalin into the plantar surface of rats and observing nociceptive behavior (flinching response) for 60 mininutes. Then, the effects of intrathecal adenosine and serotonin receptor antagonists on the antinociceptive activity of intrathecal sildenafil were examined.

Results

Intrathecal sildenafil suppressed the flinching response in a dose-dependent manner during phases 1 and 2 in the formalin test. Both CGS 15943 and dihydroergocristine decreased the antinociceptive effects of sildenafil during phases 1 and 2 in the formalin test.

Conclusion

Intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Both adenosine and serotonin receptors may be involved in the antinociceptive action of sildenafil at the spinal level.     

Synergistic effects between intrathecal clonidine and neostigmine in the formalin test

Spinal alpha-2 adrenoceptors and cholinergic receptors are involved in the regulation of acute nociception and the facilitated processing. The aim of this study was to examine the pharmacological effect of an intrathecal alpha-2 agonist and a cholinesterase inhibitor on the facilitated pain model induced by formalin injection and to determine the nature of drug interaction using an isobolographic analysis. Both intrathecal clonidine and neostigmine dose-dependently suppressed the flinching during phase 1 and phase 2. Intrathecal pretreatment with atropine reversed the antinociceptive effects of clonidine and neostigmine in both phases. Pretreatment with intrathecal yohimbine attenuated the effect of clonidine. The antinociception of clonidine and neostigmine was not reversed by mecamylamine. Isobolographic analysis showed that intrathecal clonidine and neostigmine acted synergistically in both phase 1 and 2. Intrathecal pretreatment with atropine and yohimbine antagonized the effect of the mixture of clonidine and neostigmine in both phases, but no antagonism was observed with mecamylamine pretreatment. These data indicate that spinal clonidine and neostigmine are effective to counteract the facilitated state evoked formalin stimulus, and these two drugs interact in a synergistic fashion. In addition, the analgesic action of intrathecal clonidine is mediated by spinal muscarinic receptors as well as alpha-2 adrenoceptors.     

Antinociceptive effects and synergistic interaction with morphine of intrathecal metabotropic glutamate receptor 2/3 antagonist in the formalin test of rats

Spinal metabotropic glutamate receptors (mGluRs) have been known to be involved in the modulation of nociception. While the antinociceptive effects of the mGluR1/5 have been demonstrated, the role of mGluR2/3 for nociception is less clear. This study investigated the effects of an intrathecal mGluR2/3 agonist, APDC, and a mGluR2/3 antagonist, LY341495, for inflammatory and acute pain in the formalin test and thermal stimulation test. We also examined their interaction with intrathecal morphine for the antinociceptive effect. APDC had little effect on the formalin-induced nociception. In contrast, LY341495 caused a dose-dependent suppression of the phase 2 flinching response to the formalin stimulus without affecting phase 1 flinching response. Furthermore, the suppression of pain behavior by LY341495 during phase 2 was reduced significantly by pretreatment with APDC. LY341495 and morphine also showed synergistic drug interaction for antinociception during phase 2 in the formalin test.     

The effects of microinjection of morphine into thalamic nucleus submedius on formalin-evoked nociceptive responses of neurons in the rat spinal dorsal horn

Previous studies have indicated that the thalamic nucleus submedius (Sm), as an ascending component, is involved in an endogenous analgesic system consisting of spinal cord-Sm-ventrolateral orbital cortex (VLO)-periaqueductal gray (PAG)-spinal cord loop. To investigate the action of opioid in this antinociception pathway, the effects of microinjection of morphine and naloxone into the Sm on the formalin-induced nociceptive responses of neurons in the spinal dorsal horn were determined in the anesthetized rat. Formalin (5%, 50 microl) subcutaneously injected into unilateral hindpaw produced a biphasic nociceptive response which was similar to that obtained from assessing the nociceptive behavior either in the relative magnitude of response or the time course. A unilateral microinjection of morphine (5 microg, 0.5 microl) into the Sm 15 min after formalin injection significantly depressed the second phasic responses of neurons induced by formalin, and this effect was significantly attenuated by pre-microinjection of opioid receptor antagonist naloxone (1 microg, 0.5 microl) into the same site. The results suggest that the Sm is involved in opioid receptor-mediated antinociceptive effect on the persistent nociception through depression of the nociceptive transmission at the spinal cord level.     

Evidence for the involvement of the mu but not delta opioid receptor subtype in the synergistic interaction between opioid and alpha 2 adrenergic antinociception in the rat spinal cord.

The interaction between the spinal antinociceptive effects of selective mu or delta opioid agonists morphine and DSTBULET (Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr), respectively, and the selective alpha 2 adrenergic agonist dexmedetomidine was examined on convergent dorsal horn neuronal responses in the intact anaesthetized rat. The coadministration of intrathecal morphine (0.5 microgram, 2.5 micrograms) and dexmedetomidine (0.5 microgram) produced a greater than additive inhibition of C fibre-evoked responses. Inhibitions were reversed by either the opioid antagonist naloxone or the alpha 2 adrenergic antagonist atipamezole. The coadministration of intrathecal DSTBULET (1 microgram, 2.5 micrograms) and dexmedetomidine did not result in a supra-additive inhibition of C fibre-evoked responses. The results suggest that mu rather than delta opioid receptors are involved in the synergism of spinal opioid and alpha 2 adrenergic antinociception.     

Ultra-low dose naloxone restores the antinociceptive effect of morphine in pertussis toxin-treated rats by reversing the coupling of μ-opioid receptors from Gs-protein to coupling to Gi-protein

Pertussis toxin (PTX) treatment results in ADP-ribosylation of Gi-protein and thus in disruption of μ-opioid receptor signal transduction and loss of the antinociceptive effect of morphine. We have previously demonstrated that pretreatment with ultra-low dose naloxone preserves the antinociceptive effect of morphine in PTX-treated rats. The present study further examined the effect of ultra-low dose naloxone on μ-opioid receptor signaling in PTX-treated rats and the underlying mechanism. Male Wistar rats implanted with an intrathecal catheter received an intrathecal injection of saline or PTX (1 μg in 5 μl of saline), then, 4 days later, were pretreated by intrathecal injection with either saline or ultra-low dose naloxone (15 ng in 5 μl of saline), followed, 30 min later, by saline or morphine (10 μg in 5 μl of saline). Four days after PTX injection, thermal hyperalgesia was observed, together with increased coupling of excitatory Gs-protein to μ-opioid receptors in the spinal cord. Ultra-low dose naloxone pretreatment preserved the antinociceptive effect of morphine, and this effect was completely blocked by the μ-opioid receptor antagonist CTOP, but not by the κ-opioid receptor antagonist nor-BNI or the δ-opioid receptor antagonist naltrindole. Moreover, a co-immunoprecipitation study showed that ultra-low dose naloxone restored μ-opioid receptor/Gi-protein coupling and inhibited the PTX-induced μ-opioid receptor/Gs-protein coupling. In addition to the anti-neuroinflammatory effect and glutamate transporter modulation previously observed in PTX-treated rats, the re-establishment of μ-opioid receptor Gi/Go-protein coupling is involved in the restoration of the antinociceptive effect of morphine by ultra-low dose naloxone pretreatment by normalizing the balance between the excitatory and inhibitory signaling pathways. These results show that ultra-low dose naloxone preserves the antinociceptive effect of morphine, suppresses spinal neuroinflammation, and reduces PTX-elevated excitatory Gs-coupled opioid receptors in PTX-treated rats. We suggest that ultra-low dose naloxone might be clinically valuable in pain management.     

Antinociceptive interactions between intrathecal gabapentin and MK801 or NBQX in rat formalin test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 microL of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.     

Lack of the nitric oxide-cyclic GMP-potassium channel pathway for the antinociceptive effect of intrathecal zaprinast in a rat formalin test

Zaprinast is a phosphodiesterase inhibitor that is active in various models of pain when administered locally. In addition, the antinociception of zaprinast is involved in the nitric oxide (NO)-cGMP pathway. However, the effect of zaprinast administered spinally has not been examined. Therefore, this study examined the effect of zaprinast on the formalin-induced nociception at the spinal level. Next, the role of the NO-cGMP-potassium channel pathway on the effect of zaprinast was further clarified. Catheters were inserted into the intrathecal space of male Sprague-Dawley (SD) rats. Pain was induced by applying 50 microl of a 5% formalin solution to the hindpaw. The change in the zaprinast-induced effect was examined after an intrathecal pretreatment with a NO synthase inhibitor (l-NMMA), a guanylyl cyclase inhibitor (ODQ) or a potassium channel blocker (glibenclamide). Zaprinast produced an antinociceptive effect during phase 1 and phase 2 in the formalin test. Intrathecal l-NMMA, ODQ and glibenclamide did not reverse the antinociception of zaprinast in either phase of the formalin test. These results suggest that zaprinast is effective against both acute pain and the facilitated pain state at the spinal level. However, the NO-sensitive cGMP-potassium channel pathway is not contributable to the antinociceptive mechanism of zaprinast in the spinal cord.     

Chronic morphine administration results in tolerance to delta opioid receptor-mediated antinociception

Delta opioid receptor agonists produce only a moderate degree of antinociception, possibly reflecting the predominantly intracellular location of delta opioid receptor. However, recent studies suggest that short term morphine pretreatment can increase delta opioid receptor-mediated antinociception by promoting the translocation of delta opioid receptor to the cell surface. Even more striking sensitization has been reported after long term morphine pretreatment and withdrawal in locomotor tests. In the present study we therefore examined the effects of longer term morphine pretreatment and withdrawal on delta opioid receptor-mediated antinociception in the formalin test. Male adult rats were pretreated daily with morphine (10 mg/kg s.c.) or saline for 10 days, and were tested acutely with the delta opioid receptor agonist [D-Ala2,Glu4]-deltorphin (intrathecal) at 0, 7 and 14 days of withdrawal. Unexpectedly, chronic morphine pre-exposure resulted in tolerance to [D-Ala2,Glu4]-deltorphin-induced antinociception, and this occurred at 0 and 7 but not 14 days of morphine withdrawal. Morphine challenge at withdrawal day 7 confirmed the presence of tolerance to the antinociceptive effects of this drug. Chronic morphine pretreatment also resulted in tolerance to the locomotor stimulant effect of [D-Ala2,Glu4]-deltorphin (given i.c.v.), contrary to a previous report of sensitization. However, consistent with previous reports, short term (2 day) pretreatment with morphine did result in sensitization to [D-Ala2,Glu4]-deltorphin. Subsequent in vitro analysis, using [125I][D-Ala2,Glu4]-deltorphin or guanosine 5'(gamma-35S-thio) triphosphate autoradiography, did not reveal any changes in delta opioid receptor binding or function resulting from chronic morphine pretreatment. In conclusion, chronic morphine pretreatment caused tolerance to delta opioid receptor-mediated behavioral effects with no clear change at the receptor level.     

Involvements of mu- and kappa-opioid receptors in morphine-induced antinociception in the nucleus accumbens of rats

It is well known that there are three types of opioid receptors, mu- (MOR), delta- (DOR), and kappa-opioid receptor (KOR) in the central nervous system. The present study investigated the involvement of opioid receptors in morphine-induced antinociception in the nucleus accumbens (NAc) of rats. The hindpaw withdrawal latencies to thermal and mechanical stimulation increased markedly after intra-NAc administration of morphine. The antinociceptive effects induced by morphine were dose-dependently inhibited by intra-NAc administration of the non-selective opioid receptor antagonist naloxone. Furthermore, the morphine-induced antinociception was significantly attenuated by subsequent intra-NAc injection of the MOR antagonist beta-funaltrexamine or the KOR antagonist nor-binaltorphimine, but not the DOR antagonist naltrindole. The results indicate that MOR and KOR, but not DOR are involved in the morphine-induced antinociception in the NAc of rats.     

Intrathecal sensory neuron-specific receptor agonists bovine adrenal medulla 8-22 and (Tyr6)-gamma2-MSH-6-12 inhibit formalin-evoked nociception and neuronal Fos-like immunoreactivity in the spinal cord of the rat

The finding that sensory neuron-specific G-protein-coupled receptor mRNA is solely expressed in small primary sensory neurons suggests involvement of the receptor in nociceptive modulation. The present study was designed to assess effects of intrathecal administration of bovine adrenal medulla 8-22 and (Tyr6)-gamma2-MSH-6-12, selective sensory neuron-specific receptor agonists, on nocifensive behaviors and expression of spinal c-Fos-like immunoreactivity evoked by intraplantar injection of 2.5% formalin in rats. The agonists were administered 10 min before (pretreatment) and/or after (post-treatment) injection of formalin. Pretreatment with bovine adrenal medulla 8-22 dose-dependently (3, 10 and 30 nmol) decreased time lifting and licking the paw mainly in the second phase. Intrathecal bovine adrenal medulla 8-22 (30 nmol) remarkably suppressed nocifensive behaviors in the first and second phases and the expression of formalin-evoked c-Fos-like immunoreactivity in laminae I-II and V-VI of the spinal dorsal horn at L4-5. Moreover, naloxone (20 microg, intrathecal) failed to antagonize the inhibitory effects of bovine adrenal medulla 8-22. Post-treatment with bovine adrenal medulla 8-22 also exerted inhibition on the second phase behaviors in a dose-dependent manner with a similar efficacy observed in pretreatment groups. Furthermore, post-treatment with (Tyr6)-gamma2-MSH-6-12 (0.5, 1.5 and 5 nmol) also suppressed formalin-evoked nocifensive behaviors in the second phase and c-Fos-like immunoreactivity in the spinal dorsal horn similar with bovine adrenal medulla 8-22. Our results suggest that sensory neuron-specific receptor may play an important role in modulation of spinal nociceptive transmission. This is the first to demonstrate that activation of sensory neuron-specific receptor produces analgesia in the persistent pain model.     

Resistance to morphine analgesic tolerance in rats with deleted transient receptor potential vanilloid type 1-expressing sensory neurons

Deletion of transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons reduces presynaptic mu opioid receptors but paradoxically potentiates the analgesic efficacy of mu opioid agonists. In this study, we determined if removal of TRPV1-expressing afferent neurons by resiniferatoxin (RTX), an ultrapotent capsaicin analog, influences the development of opioid analgesic tolerance. Morphine tolerance was induced by daily intrathecal injections of 10 microg of morphine for 14 consecutive days or by daily i.p. injections of 10 mg/kg of morphine for 10 days. In vehicle-treated rats, the effect of intrathecal or systemic morphine on the mechanical withdrawal threshold was gradually diminished within 7 days. However, the analgesic effect of intrathecal and systemic morphine was sustained in RTX-treated rats at the time the morphine effect was lost in the vehicle group. Furthermore, the mu opioid receptor-G protein coupling in the spinal cord was significantly decreased ( approximately 22%) in vehicle-treated morphine tolerant rats, but was not significantly altered in RTX-treated rats receiving the same treatment with morphine. Additionally, there was a large reduction in protein kinase Cgamma-immunoreactive afferent terminals in the spinal dorsal horn of RTX-treated rats. These findings suggest that loss of TRPV1-expressing sensory neurons attenuates the development of morphine analgesic tolerance possibly by reducing mu opioid receptor desensitization through protein kinase Cgamma in the spinal cord. These data also suggest that the function of presynaptic mu opioid receptors on TRPV1-expressing sensory neurons is particularly sensitive to down-regulation by mu opioid agonists during opioid tolerance development.     

Involvement of mu- and delta-opioid receptors in the antinociceptive effects induced by AMPA receptor antagonist in the spinal cord of rats

The present study was performed to explore the involvement of opioid receptors in the antinociception induced by a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor antagonist in rats. The hindpaw withdrawal latency (HWL) to noxious thermal and mechanical stimulation was assessed by hot plate test and the Randall Selitto Test. Intrathecal injection of 20 nmol of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo[f]quinoxaline-7-sulfonamide (NBQX) disodium, a competitive AMPA receptor antagonist, increased significantly the HWLs to both thermal and mechanical stimulation in rats. The increased HWLs induced by NBQX were dose-dependently attenuated by the opioid receptor antagonist naloxone, while naloxone itself had no marked influences on the HWL of rats. Furthermore, the increased HWLs induced by NBQX were inhibited by the mu-opioid antagonist beta-funaltrexamine (beta-FNA) or the delta-opioid antagonist naltrindole, but not by the kappa-opioid antagonist nor-binaltorphimine (nor-BNI). The results suggest that mu- and delta-opioid receptors, not kappa-opioid receptor, are involved in the antinociception induced by AMPA antagonist in the spinal cord of rats.     

A peripheral, intracerebral, or intrathecal administration of an opioid receptor antagonist blocks illness-induced hyperalgesia in the rat

We used the tail-flick response of rats to study the role of opioid receptors in illness-induced hyperalgesia. An intraperitoneal injection of lithium chloride (LiCl) produced hyperalgesia that was blocked in a dose-dependent manner by subcutaneous injection of the opioid antagonist naloxone. Neither hyperalgesia nor its blockade by naloxone were due to variations in tail-skin temperature induced by LiCl. Hyperalgesia was also blocked when opioid receptor antagonism was restricted to (a) the periphery, by intraperitoneal administration of the quaternary opioid receptor antagonist naloxone methiodide; (b) the brain, by intracerebroventricular microinjection of naloxone; or (c) the spinal cord, by intrathecal microinjection of naloxone. These results document a pain facilitatory role of opioid receptors in both the peripheral and central nervous systems and are discussed with reference to their analgesic and motivational functions.