Involvement of oxytocin in spinal antinociception in rats with inflammation

The present study was conducted on rats with inflammation induced by subcutaneous injection of carrageenan into the left hindpaw. Intrathecal administration of oxytocin produced dose-dependent increases in the hindpaw withdrawal latency (HWL) to thermal and mechanical stimulation in rats with inflammation. The antinociceptive effect of oxytocin was blocked by intrathecal administration of atosiban, a selective oxytocin antagonist, indicating that oxytocin receptor mediates oxytocin-induced antinociception in the spinal cord. The oxytocin-induced antinociceptive effect was attenuated by intrathecal administration of the opioid antagonist naloxone, suggesting an involvement of the endogenous opioid system in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Furthermore, the antinociceptive effect of oxytocin was attenuated by intrathecal injections of the mu-receptor antagonist beta-funaltrexamine and the kappa-receptor antagonist nor-binaltorphimine, but not by the delta-receptor antagonist naltrindole, illustrating that mu- and kappa-receptors, but not delta-receptor, are involved in oxytocin-induced antinociception in the spinal cord of rats with inflammation. Moreover, intrathecal administration of atosiban alone induced a hyperalgesia in rats with inflammation, indicating that endogenous oxytocin is involved in the transmission and regulation of nociceptive information in the spinal cord of rats with inflammation. The present study showed that both exogenous and endogenous oxytocin displayed antinociception in the spinal cord in rats with inflammation, and mu- and kappa-receptors were involved in oxytocin-induced antinociception.     

Pro-nociceptin/orphanin FQ and NOP receptor mRNA levels in the forebrain of food deprived rats

Forebrain injections of nociceptin/orphanin FQ (N/OFQ), the endogenous ligand of the NOP opioid receptor, previously referred to as ORL1 or OP4 receptor, stimulate feeding in freely feeding rats, while the NOP receptor antagonist [Nphe(1)]N/OFQ(1-13)NH(2) inhibits food deprivation-induced feeding. To further evaluate whether the N/OFQ-NOP receptor system plays a physiological role in feeding control, the present study evaluated forebrain mRNA levels for the N/OFQ precursor (pro-N/OFQ), as well as for the NOP receptor in food deprived rats. The results obtained show that food deprived rats have lower mRNA levels for the NOP receptor in several forebrain regions; a significant reduction was found in the paraventricular and lateral hypothalamic nuclei and in the central nucleus of the amygdala. Food deprived rats also exhibited lower pro-N/OFQ mRNA levels in the central amygdala. These results suggest that the N/OFQ-NOP receptor system may have a physiological role in feeding control. The observation that food deprivation reduces gene expression of the N/OFQ-NOP receptor system is apparently not consistent with a direct hyperphagic action for N/OFQ. Taking into account that N/OFQ exerts inhibitory actions at cellular level, the present results may be in keeping with the hypothesis that N/OFQ stimulates feeding by inhibiting neurons inhibitory for food intake; under conditions of food deprivation, these neurons may be silent and the N/OFQ-NOP receptor system, which controls them, may also be regulated at a lower level. Consistently, in the present study N/OFQ stimulated food intake in freely feeding rats, but did not further increase feeding in food deprived rats.     

Basal levels and alcohol-induced changes in nociceptin/orphanin FQ, dynorphin, and enkephalin levels in C57BL/6J mice

In order to investigate the involvement of the opioid and nociceptin/orphanin FQ (N/OFQ) system in alcohol drinking behaviour, N/OFQ and the opioid peptides dynorphin B (DYNB) and Met-enkephalin-Arg(6) Phe(7) (MEAP) were examined in the alcohol-preferring C57BL/6J mice. Basal peptide levels were compared in the brain and the pituitary gland with basal levels in the alcohol-avoiding DBA/2J mice. Furthermore, the effects of chronic alcohol self-administration on peptides were studied in the C57BL/6J mice. Compared to the DBA/2J mice, C57BL/6J mice had low immunoreactive (ir) levels of DYNB and MEAP in the nucleus accumbens, the hippocampus, and the substantia nigra, low ir-DYNB levels in the striatum and low ir-MEAP levels in the frontal cortex. Higher ir-DYNB levels in the pituitary gland and in the periaqueductal gray (PAG) and higher ir-N/OFQ levels in the frontal cortex and in the hippocampus were detected in C57BL/6J mice compared to the DBA/2J mice. After 4 weeks of voluntary alcohol consumption, only minor changes in steady-state peptide levels were identified. However, 5 days after the alcohol-drinking period, lower levels of all peptides were detected in the ventral tegmental area and ir-DYNB levels were also lower in the amygdala and in the substantia nigra. Twenty-one days after cessation of alcohol self-administration, the opioid peptides in alcohol-consuming C57BL/6J mice were lower in the PAG, the N/OFQ was lower in the frontal cortex and DYNB was higher in the amygdala and substantia nigra as compared to control C57BL/6J mice. This study demonstrates strain differences between C57BL/6J mice and DBA/2J mice that could contribute to divergent drug-taking behaviour, and it also demonstrates time- and structure-specific changes in neuropeptide levels after alcohol self-administration in the C57BL/6J mice.     

Fos expression in feeding-related brain areas following intracerebroventricular administration of orphanin FQ in rats

While the influence of orphanin FQ (OFQ) on the regulation of food intake has been substantiated, little is known about feeding-related brain regions that mediate OFQ-induced feeding. To further investigate this, we injected OFQ intracerebroventricularly and evaluated c-Fos immunoreactivity in brain areas thought to be involved in the regulation of food intake. Altered c-Fos expression as a consequence of OFQ injection was observed in the nucleus of the solitary tract, paraventricular nucleus of the hypothalamus, supraoptic nucleus, central nucleus of amygdala, lateral septal nucleus and lateral habenular nucleus. Presumably, OFQ modulates food ingestion through its action on these brain regions, most probably by activating feeding signals as well as suppressing satiety mechanisms.     

Quantitative autoradiographic mapping of the ORL1, μ-, δ- and κ-receptors in the brains of knockout mice lacking the ORL1 receptor gene

Until recently the opioid receptor family was thought to consist of only the μ-, δ- and κ-receptors. The cloning of opioid receptor like receptor (ORL1) and its endogenous ligand nociceptin/orphanin FQ, which displayed anti-opioid properties, has raised the issue of functional co-operativity of this system with the classical opioid system. ORL1 receptor knockout mice have been successfully developed by homologous recombination to allow the issue of potential heterogeneity of this receptor and also of compensatory changes in μ-, δ- or κ-receptors in the absence of ORL1 to be addressed. We have carried out quantitative autoradiographic mapping of these receptors in the brains of mice that are wild-type, heterozygous and homozygous for the deletion of the ORL1 receptor. ORL1, μ-, δ- and κ-receptors were labelled with [³H] leucyl-nociceptin (0.4 nM), [³H] DAMGO (4 nM), [³H] deltorphin-I (7 nM), and [³H] CI-977 (2.5 nM) respectively. An approximately 50% decrease in [³H] leucyl-nociceptin binding was seen in heterozygous ORL1 mutant mice and there was a complete absence of binding in homozygous brains indicating the single gene encodes for the ORL1 receptor and any putative subtypes. No significant gross changes in the binding to other opioid receptors were seen across genotypes in the ORL1 mutant mice demonstrating a lack of major compensation of classical opioid receptors in the absence of ORL1. There were a small number of region specific changes in the expression of classical opioid receptors that may relate to interdependent function with ORL1.     

Anxiolytic-like effect of central administration of NOP receptor antagonist UFP-101 in rats submitted to the elevated T-maze

Depression and anxiety disorders present several genetic and neurobiological similarities. Drugs with antidepressant activity are effective in the treatment of a wide spectrum of anxiety disorders. Preclinical results showed that acute and chronic treatment with the NOP antagonist [Nphe¹,Arg¹⁴,Lys¹⁵]N/OFQ-NH₂ (UFP-101) produced antidepressant-like effects in rodents. Thus, the present study aimed to investigate the effect of central administration of UFP-101 on the anxiety-related behavior in rats as evaluated in the elevated T-maze (ETM) test. Our results showed that UFP-101 reduced the latency of inhibitory avoidance in the ETM, indicating an anxiolytic-like effect. The endogenous peptide N/OFQ prevented this anxiolytic-like action of UFP-101, demonstrating its modulation via central NOP receptors. However, UFP-101 failed to interfere with the latency to escape. No change was observed in locomotor activity after UFP-101 treatment, ruling out any nonspecific motor effect. In conclusion, our results showed that the central administration of UFP-101 presents an anxiolytic-like effect in rats evaluated in the ETM test, providing new insights for drug development to treat anxiety disorders targeting the N/OFQ-NOP receptor system.     

It is AMPA receptor, not kainate receptor, that contributes to the NBQX-induced antinociception in the spinal cord of rats

Studies demonstrated that intrathecal 1,2,3,4-tetrahydro-6-nitro-2, 3-dioxo[f]quinoxaline-7-sulfonamide disodium (NBQX), an antagonist of AMPA/kainate receptors, induced antinociception in the spinal cord of rats. The present study demonstrated that the NBQX-induced increases in hindpaw withdrawal latencies (HWLs) were dose-dependently attenuated by intrathecal pretreatment of the AMPA receptor desensitization inhibitor, diazoxide. The effect was unrelated to the opening of K+ channels by diazoxide. On the other hand, intrathecal pretreatment of concanavalin A, which selectively inhibits the desensitization of kainate receptor, produced no significant influence on the NBQX-induced antinociception. The results suggest that the NBQX-induced antinociception was mediated by AMPA receptors, not by kainate receptors, in the spinal cord of rats.     

Involvement of tachykinin NK1 receptors in nociceptin-induced hyperalgesia in mice

Intrathecal (i.t.) injection of nociceptin at small doses (3.0 and 30.0 fmol) produced a significant hyperalgesic response as assayed by the tail-flick test. This hyperalgesic effect peaked at 15 min following i.t. administration of nociceptin (3.0 fmol) and returned to control level within 30 min. Hyperalgesia elicited by nociceptin was inhibited dose-dependently by i.t. co-administration of tachykinin NK₁ receptor antagonists, CP-99,994 and sendide. A significant antagonistic effect of [ -Phe⁷, -His⁹] substance P (6–11), a selective antagonist for substance P, was observed against the nociceptin-induced hyperalgesia. Pretreatment with i.t. substance P antiserum and i.t. capsaicin resulted in a complete block of the reduced threshold produced by nociceptin. The NK₂ receptor antagonist, MEN-10,376 and pretreatment with neurokinin A antiserum did not alter the behavioural effect of nociceptin. The N-methyl- -aspartate (NMDA) receptor antagonists, dizocilpine (MK-801) and (−)-2-amino-5-phosphonovaleric acid ( -APV), and -N^G-nitro arginine methyl ester ( -NAME), a nitric oxide synthase inhibitor, failed to inhibit nociceptin-induced hyperalgesia. The results obtained suggest that the hyperalgesic effect of nociceptin may be mediated through tachykinin NK₁ receptors in the spinal cord.     

Development of opioid systems: peptides, receptors and pharmacology

The understanding of opioid system function in the adult has progressed markedly in the last decade. This in turn has led to an increased knowledge of how opioid function develops in the embryo and in the postnatal period.With respect to the ontogenetic profile of the opioid peptide products of the 3 opioid precursors, all are detectable during gestation and their development in rodents is not completed until well after birth, the third postnatal week often exhibiting the most marked increases. There is not an exact parallel development of the precursors and there may be regional fluctuations for some of the peptides in the postnatal period. All of the indications are that the ontogenesis of the 3 precursors occurs independent ly, and that their opioid peptide products have distinct ontogenetic profiles (Section 2.2.–2.4.). Indeed in a comparative immunocytochemical study for dynorphin-A and enkephalin³⁶ the patterns of deveopment in the hippocampal formation were dissimilar. In addition the differences observed in ontogenetic patterns for the precursor products may well reflect differential activities of the processing cleavage enzymes in the developing animal. Indeed a comparative ontogenetic study of ACTH and β-endorphin^64,65 showed a dissimilar profile during early development in rat brain and pituitary. Whilst these may be due to different processing patterns, the possibility of differential release, secretion or degradation of these peptides cannot be excluded and may be independent of the synthesis of the precursor.There is also a differential ontogeny of the opioid receptor subtypes and the recent evidence with highly selective binding ligands has provided a clear pattern, μ- And κ-sites are the first to appear though δ-receptors are absent until the second postnatal week in the rat. In this species the full development of μ- and δ-sites occurs in the third and fourth weeks respectively.There is still some argument about the ontogenetic profile for κ-sites though, like the δ-receptors, full development is probably later than for the μ-sites. Ontogenetic profiles of opioid receptors have also been demonstrated in the chick, sheep and mouse. Too few studies have looked at peptide and recep tor development in parallel and it is still unclear if specific peptide development is directly linked with development of a single receptor site.The postnatal development of both opioid peptides and receptors is mirrored by pharmacological actions of opioids which differ in the neonate. Their pharmacological effects are not solely dependent on the number of receptors but also on the ontogenetic pattern of the metabolising enzymes and on bloodbrain barrier development. There are some anomalous responses to opioids in the neonate and these include locomotion, respiratory depressant activity and effects on corticosterone release.There are also indications that the opioid system is particularly sensitive to insult during the developing period. In particular toxic effects at low doses have been shown for lead exposure, diazepam and haloperidol treatment. It may be that the complexity of opioid function increases the risk of disruption or it may reflect a ubiquitous involvement of the endogenous opioid peptides in the control of several neurochemica in the brain.The future needs more studies in animals other than the rat and a clearer picture of the genetic profile of the precursors and the processing of the same during development. This information should not be long in coming.     

Effects of melatonin on orphanin FQ/nociceptin-induced hyperalgesia in mice

The pain modulatory properties of melatonin (MT) are generally recognized but the detail of the interaction between melatonin and opioid system in pain regulation is not fully understood. The present study was undertaken to investigate the modulatory effect of melatonin (MT) on the hyperalgesic effect of Orphanin FQ/Nociceptin (OFQ/NC, NC), a member of opioid peptide family. Intracerebroventricular (i.c.v.) administration of NC (10 microg/mouse) induced significant hyperalgesic effect in tail-flick test in mice; i.c.v. (5, 10, 50 microg/mouse) or intraperitoneal (i.p.) (5, 10, 50 mg/kg) co-injection of melatonin dose-dependently reversed NC-induced hyperalgesia and showed a profound analgesic effect. The antihyperalgesia effect of MT could be significantly antagonized by i.c.v. co-injection of luzindole (10 microg/mouse) (an antagonist of MT receptor) or naloxone (10 microg/mouse) (antagonist of traditional opioid receptor). Taken together, all the results suggested that MT could produce a luzindole and naloxone sensitive reversing effect on NC-induced hyperalgesia at supraspinal and peripheral level in mice. The augmentation effect of MT on the traditional opioid system may be one of the mechanisms of this antihyperalgesia action induced by MT. The present work will help to elucidate the mechanism of the pain modulation effect of MT, and also will help to represent new interesting modulating therapeutic targets for the relief of pain.     

Nociceptin attenuates methamphetamine abstinence-induced withdrawal-like behavior in planarians

Planarians display a concentration-related reduction in locomotor activity when amphetamine, cocaine, cannabinoid, or benzodiazepine exposure is abruptly discontinued. In the present study, we tested the hypothesis that abrupt discontinuation of methamphetamine would also cause withdrawal-like behavior in planarians and that the withdrawal-like behavior would be prevented by nociceptin, which has been shown to modulate the effects of methamphetamine in mammals. We observed a concentration-related reduction of locomotor behavior when planarians exposed to methamphetamine (0.1-100 microM) were tested in drug-free water. The withdrawal-like behavior was abolished when methamphetamine (10 microM)-exposed planarians were placed into water containing nociceptin (10 microM) or when planarians co-exposed to methamphetamine (10 microM) and nociceptin (10 microM) were placed into drug-free water. The effects of nociceptin were abolished in the presence of a nociceptin receptor antagonist, JTC-801 (1 microM). Planarians did not display a change in locomotor behavior during exposure to nociceptin (10 microM) or JTC-801 (1 microM) by themselves. These results (1) reveal a functional interaction between nociceptin and methamphetamine in planarians and (2) provide evidence that nociceptin blocks methamphetamine-induced withdrawal-like behavior in planarians through a JTC-801-sensitive mechanism.     

Effect of intrathecal nocistatin on nociceptin/orphanin FQ analgesia in chronic constriction injury rat

Nocistatin and nociceptin/orphanin FQ (N/OFQ) are two neuropeptides derived from the same precursor protein, prepronociceptin (ppOFQ), and exhibit different effects on spinal neurotransmission. Nocistatin does not bind to nociceptin/orphanin FQ peptide receptor (NOP), but intrathecal (i.t.) nocistatin has been reported to block the analgesic effect of i.t. N/OFQ. In this study, we investigated the effect of i.t. nocistatin on N/OFQ analgesia to radiant thermal stimuli in chronic constriction injury (CCI) rat. Firstly, to investigate the analgesic effect of N/OFQ, different doses of N/OFQ (3, 10, 30 microg) were intrathecally injected and foot withdrawal latency (FWL) to radiant heat was recorded. It is observed that 3 microg N/OFQ had no effect on FWL, 10 and 30 microg N/OFQ significantly increased FWL of CCI rat. Then, 10 microg N/OFQ, 10 microg nocistatin and a drug cocktail including 10 microg N/OFQ and 10 microg nocistatin were intrathecally injected. The results showed that FWL significantly decreased after using N/OFQ and nocistatin compared with using only N/OFQ, and 10 microg nocistatin had no effect on FWL versus control, suggesting that this dose of nocistatin per se had no effect on the pain threshold of CCI rat, but could block the analgesic effect of N/OFQ. These results indicated that i.t. N/OFQ dose-relatedly depressed thermal hyperalgesia produced by CCI and nocistatin could block N/OFQ analgesia at spinal level in CCI rat.     

Distribution of nociceptin/orphanin FQ in adult human brain

Nociceptin/orphanin FQ (N/OFQ), the endogenous agonist for the opioid receptor-like receptor 1 (ORL1), shows significant similarities to dynorphin A in structure and distribution in rat central nervous system. The distribution of N/OFQ in human brain has not been studied. We measured the concentrations of N/OFQ in 47 microdissected areas of the central nervous system of adult human brain using radioimmunoassay (RIA). Significant heterogeneity was found in the levels of N/OFQ concentration in the various analyzed regions. The highest concentrations were measured in the dorsal central gray matter (periaqueductal gray), the locus coeruleus, the ventromedial nucleus of hypothalamus, the septum and the dorsal horn of the spinal cord. High concentrations were also detected in other hypothamamic nuclei, the inferior colliculus, the ventral central gray matter, the pontine tegmentum, the amygdala, the reticular formation and the spinal trigeminal nucleus. Considerable similarity with the distribution of N/OFQ in rat CNS was observed. The widespread distribution in CNS predicts multifaceted functions for N/OFQ.     

Differential antinociception by morphine and methadone in two sub-strains of Sprague-Dawley rats and its potentiation by dextromethorphan

The antinociceptive effect of morphine and methadone was tested in two substrains of Sprague-Dawley (SD) rats, from B&K Universal, Sweden (BK) and Molleg?rd, Denmark (DK). In both sub-strains of SD rats subcutaneous morphine or methadone produced dose-dependent antinociception on the hot plate test. However, the effect of the opioids was less in DK-SD than BK-SD rats, particularly for morphine as it failed to produce maximal antinociception even at high doses. Dextromethorphan, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, potentiated the antinociceptive effect of morphine and methadone in the DK-SD rats. The potentiation of morphine by dextromethorphan was significantly greater than its effect on methadone at equipotent doses. The results showed that there is a sub-strain difference for SD rats in the response to the antinociceptive effect of opioids, which may be due to greater NMDA receptor activity in DK-SD than in BK-SD rats. The higher efficacy of methadone may be derived from its proposed NMDA receptor blocking property and/or high intrinsic activity.     

Involvement of endogenous opioids and ATP-sensitive potassium channels in the mediation of carbachol-induced antinociception at the spinal level: a behavioral study in rats

The effects of intrathecally administered (i.t.) atropine, glibenclamide, a blocker of ATP-sensitive potassium channels, or naloxone on the antinociception produced by i.t. carbachol or morphine were observed in rats by tail-flick (TF) test. The results showed that: (1) i.t. carbachol produced a dose-dependent antinociception and it could be antagonized by i.t. atropine; (2) the antinociception produced by i.t. carbachol could be blocked dose-dependently by i.t. glibenclamide or i.t. naloxone; (3) the antinociception produced by i.t. morphine could be blocked dose-dependently by i.t. glibenclamide, but not by i.t. atropine. The results suggest that the antinociception produced by activation of muscarinic receptors at the spinal level might be mediated by endogenous opioids and ATP-sensitive potassium channels in a cascade from.     

The novel neuropeptide orphanin FQ fails to produce conditioned place preference or aversion

An unbiased conditioned place preference procedure was used to determine whether the newly-identified neuropeptide orphanin FQ produced motivational effects after intracerebroventricular microinjections. Microinjections of orphanin FQ (0.1–100 nmol) failed to produce conditioned place preference or aversion, but a pronounced motor impairment was observed during conditioning sessions with the two highest doses. Thus, it appears that orphanin FQ lacks motivational effects when administered at behaviourally active doses.     

Polyarthritis-associated changes in the opioid control of spinal CGRP release in the rat

As a model of chronic inflammatory pain, Freund's adjuvant-induced polyarthritis has been shown to be associated with marked alterations in the activity of opioid- and calcitonin gene-related peptide (CGRP)-containing neurons in the dorsal horn of the spinal cord in rats. Possible changes in the interactions between these two peptidergic systems in chronic inflammatory pain were investigated by comparing the effects of various opioid receptor ligands on the spinal outflow of CGRP-like material (CGRPLM) in polyarthritic and age-paired control rats. Intrathecal perfusion of an artificial cerebrospinal fluid in halothane-anaesthetized animals allowed the collection of CGRPLM released from the spinal cord and the application of opioid receptor ligands. The blockade of κ-opioid receptors similarly increased CGRPLM release in both groups of rats as expected of a κ-mediated tonic inhibitory control of CGRP-containing fibres in control, as well as in polyarthritic rats. In contrast, the higher increase in CGRPLM outflow due to the preferential blockade of μ opioid receptors by naloxone in polyarthritic rats as compared to non-suffering animals supports the idea of a reinforced μ opioid receptor-mediated tonic inhibitory control of CGRP-containing fibres in rats suffering from chronic pain. Even more strikingly, the differences observed in the effects of ∂-opioid receptor ligands on CGRPLM outflow suggest that ∂ receptors are functionally shifted from a participation in a phasic excitatory control in non-suffering rats to a tonic inhibitory control in polyarthritic rats. These data indicate that agonists acting at the three types of opioid receptors all exert a tonic inhibitory influence on CGRP-containing nociceptive primary afferent fibres within the spinal cord of polyarthritic rats. Such a convergence probably explains why morphine and other opioids are especially potent to reduce pain in subjects suffering from chronic inflammatory diseases.     

Periaqueductal gray stimulation produces a spinally mediated, opioid antinociception for the inflamed hindpaw of the rat

The objective of the present study was to characterize stimulation-produced antinociception from the periaqueductal gray matter (PAG) in rats with unilateral hindlimb inflammation induced by an intraplantar injection of Freund's complete adjuvant. Rats were chronically implanted with a bipolar stimulating electrode in the PAG. Nociception was assessed using a paw pressure test. Prior to inflammation, PAG stimulation significantly increased paw pressure threshold in both paws compared to non-stimulated controls. Following inflammation, PAG stimulation inhibited nociception in the inflamed, but not the non-inflamed paw. Systemic administration of naloxone blocked antinociception from ventral, but not dorsal PAG stimulation sites. Intrathecal, but not subcutaneous, administration of quaternary naltrexone completely blocked stimulation-produced antinociception from the PAG. The known increased levels of endogenous opioids occurring in the spinal cord ipsilateral to the site of inflammation suggest a mechanism for the selective antinociceptive effect of ventral PAG stimulation seen for the inflamed paw.     

NMDA and opioid receptors: their interactions in antinociception, tolerance and neuroplasticity

Over the last several years, significant progress has been made in our understanding of interactions between the N-methyl--aspartate (NMDA) and opioid receptors. Such interactions have been demonstrated at two distinct sites: (1) modulation of NMDA receptor-mediated electrophysiological events by opioids; and (2) intracellular events involving interactions between NMDA and opioid receptors. Furthermore, a considerable number of studies have shown the involvement of such interactions in neural mechanisms of nociceptive transmission, antinociception in acute and chronic pain states, opioid tolerance/dependence, and neuroplasticity. Importantly, emerging evidence indicates that activation of NMDA receptors may differentially modulate functions mediated by distinct opioid receptor subtypes, namely μ, δ, and κ receptors. These studies have greatly enriched our knowledge regarding both NMDA and opioid receptor systems and have shed light on neurobiology of both acute and chronic pain. The advancement of such knowledge also promotes new strategies for better clinical management of pain patients.