Role Of Opioid Receptor Subtypes Research Articles

The Role of Cardiac Opioid Receptors in the Cardioprotective Effect of Continuous Normobaric Hypoxia.

We studied the role of opioid receptor subtypes in improvement of the functional state of the heart during reperfusion after adaptation to continuous normobaric hypoxia. To this end, male Wistar rats were subjected to continuous normobaric hypoxia (12% O2). Then, the hearts were isolated and exposed to total 45-min ischemia followed by 30-min reperfusion. Opioid receptor antagonists were added to the perfusion solution prior to ischemia. It was found that continuous normobaric hypoxia reduced the release of creatine phosphokinase into the effluent, increased myocardial contractile force, and decreased the end-diastolic pressure during reperfusion; these positive effects were related to activation of cardiac δ2- and μ-opioid receptors.

Activating mu-opioid receptors in the spinal cord mediates the cardioprotective effect of remote preconditioning of trauma.

Remote precoditioning of trauma (RPCT) confers cardioprotective effects against myocardial ischemia/reperfusion injury, which are mediated by spinal opioid receptors. The aim of this study was to identify the roles of opioid receptor subtypes in the cardioprotective effect of RPCT and possible mechanisms. In this study, 192 Sprague-Dawley rats were allocated to 12 groups. Except for the sham group, rats in all groups were subjected to myocardial ischemia reperfusion. Rats in the ischemia precondition (IPC) group were treated with IPC. In the RPCT groups, an abdominal incision was made 15 min before inducing ischemia. The selective delta-, kappa-, and mu-opioid receptor antagonists were administered to groups of animals receiving RPCT, respectively. Data were collected for myocardial infarct size, intercellular adhesion molecule 1 (ICAM-1), plasma cardiac troponin I (cTnI) concentrations, activation of protein kinase C epsilon (PKCe) in myocardial cell membranes, and adenosine release in the spinal cord. Compared with the control groups, infarct size, plasma concentrations of cTnI, and myocardial ICAM-1 expression were significantly lower, while adenosine release and PKCe activation were enhanced in the IPC and RPCT groups. Compared with the RPCT group, infarct size, plasma cTnI concentration, and myocardial ICAM-1 expression were greater and adenosine release and PKCe activation were reduced in the mu-opioid receptor antagonist plus RPCT group. The spinal mu-opioid receptor mediated the cardiac protective effect of RPCT. The mechanism may be enhanced by adenosine release in the spinal cord and PKCe activation in the myo-cardium, thereby inhibiting inflammation induced by ischemia/reperfusion injury.

Roles of Opioid Receptor Subtype in the Spinal Antinociception of Selective Cyclooxygenase 2 Inhibitor

BackgroundSelective inhibitors of cyclooxygenase (COX)-2 are commonly used analgesics in various pain conditions. Although their actions are largely thought to be mediated by the blockade of prostaglandin (PG) biosynthesis, evidences suggesting endogenous opioid peptide link in spinal antinociception of COX inhibitor have been reported. We investigated the roles of opioid receptor subtypes in the spinal antinociception of selective COX-2 inhibitor.MethodsTo examine the antinociception of a selective COX-2 inhibitor, DUP-697 was delivered through an intrathecal catheter, 10 minutes before the formalin test in male Sprague-Dawley rats. Then, the effect of intrathecal pretreatment with CTOP, naltrindole and GNTI, which are µ, δ and κ opioid receptor antagonist, respectively, on the analgesia induced by DUP-697 was assessed.ResultsIntrathecal DUP-697 reduced the flinching response evoked by formalin injection during phase 1 and 2. Naltrindole and GNTI attenuated the antinociceptive effect of intrathecal DUP-697 during both phases of the formalin test. CTOP reversed the antinociception of DUP-697 during phase 2, but not during phase 1.ConclusionsIntrathecal DUP-697, a selective COX-2 inhibitor, effectively relieved inflammatory pain in rats. The δ and κ opioid receptors are involved in the activity of COX-2 inhibitor on the facilitated state as well as acute pain at the spinal level, whereas the µ opioid receptor is related only to facilitated pain.

Roles of opioid receptor subtypes in mediating alcohol‐seeking induced by discrete cues and context

The aim of this study was to assess the effects of selective blockade of the delta (DOP) or mu (MOP) opioid receptors on alcohol-seeking induced by discrete cues and context. In Experiment 1, rats were trained to self-administer alcohol in an environment with distinct sensory properties. After extinction in a different context with separate sensory properties, rats were tested for context-induced renewal in the original context following treatment with the DOP receptor antagonist naltrindole (0-15 mg/kg, i.p.) or the MOP receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) (0-3 microg/4 microL, i.c.v.). In Experiment 2, reinstatement was tested with the presentation of a discrete light + tone cue previously associated with alcohol delivery, following extinction without the cue. The effects of naltrindole (0-5 mg/kg, i.p.) or CTOP (0-3 microg/4 microL, i.c.v.) were assessed. For context-induced renewal, 7.5 mg/kg naltrindole reduced responding without affecting locomotor activity. Both doses of CTOP attenuated responding in the first 15 min of the renewal test session; however, total responses did not differ at the end of the session. For discrete-cue-induced reinstatement, 1 and 5 mg/kg naltrindole attenuated responding but CTOP had no effect. We conclude that whereas DOP receptors mediate alcohol-seeking induced by discrete cues and context, MOP receptors may play a modest role only in context-induced renewal. These findings point to a differential involvement of opioid receptor subtypes in the effects of different kinds of conditioned stimuli on alcohol-seeking and support a more prominent role for DOP receptors.

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.

Central κ-opioid receptor-mediated antidepressant-like effects of nor-Binaltorphimine: Behavioral and BDNF mRNA expression studies

κ-opioid receptor antagonists such as nor-Binaltorphimine (nor-BNI) have been shown to produce antidepressant-like behavioral effects in animal models of depression. The aim of this study was to investigate further the duration of centrally administered nor-BNI-induced antidepressant-like actions measured by both behavior and brain-derived neurotrophic factor (BDNF) gene expression. In addition, antagonist studies were conducted to determine the role of opioid receptor subtypes and the time course of nor-BNI's pharmacological actions. Antidepressant-like behavioral effects were measured by decreased immobility in the rat forced swim test and BDNF mRNA expression was determined by in situ hybridization. Centrally administered nor-BNI (20 μg, i.c.v.) decreased immobility and increased BDNF mRNA expression in the hippocampus on day 1, not on days 3–14, post-administration. Systemic administration of selective μ-, δ- and κ-opioid receptor antagonists did not block nor-BNI-induced antidepressant-like effects. In contrast, i.c.v. administration of nor-BNI 7 or 14 days earlier significantly blocked subsequent nor-BNI-induced decreased immobility and upregulation of BDNF mRNA expression. Although the duration of nor-BNI's antidepressant-like effects did not synchronize with that of its κ-opioid receptor antagonist effects, this study is the first to show that centrally administered nor-BNI, like most clinically used antidepressants, can upregulate BDNF mRNA expression in the rat hippocampus. These findings further demonstrate that central κ-opioid receptor mediates antidepressant-like effects of nor-BNI measured by both behavior and BDNF gene expression.

Atypical anxiolytic-like response to naloxone in benzodiazepine-resistant 129S2/SvHsd mice: role of opioid receptor subtypes

Mice of many 129 substrains respond to environmental novelty with behavioural suppression and high levels of anxiety-like behaviour. Although resistant to conventional anxiolytics, this behavioural phenotype may involve stress-induced release of endogenous opioids. To assess the effects of opioid receptor blockade on behavioural reactions to novelty stress in a chlordiazepoxide-resistant 129 substrain. Experiment 1 contrasted the effects of the broad-spectrum opioid receptor antagonist naloxone (1.0-10.0 mg/kg) in C57BL/6JOlaHsd and 129S2/SvHsd mice exposed to the elevated plus-maze. Experiments 2-4 examined the responses of 129S2/SvHsd mice to the mu-selective opioid receptor antagonist beta-funaltrexamine (2.5-10.0 mg/kg), the delta-selective antagonist naltrindole (2.5-10.0 mg/kg) and the kappa-selective antagonist nor-binaltorphimine (2.5-5.0 mg/kg). 129 mice displayed higher levels of anxiety-like behaviour and lower levels of general exploration relative to their C57 counterparts. Although naloxone failed to alter the behaviour of C57 mice, both doses of this antagonist produced behaviourally selective reductions in open-arm avoidance in 129 mice. Surprisingly, none of the more selective opioid receptor antagonists replicated this effect of naloxone: beta-funaltrexamine was devoid of behavioural activity, naltrindole suppressed rearing (all doses) and increased immobility (10 mg/kg), while nor-binaltorphimine (5 mg/kg) nonspecifically increased percent open arm entries. Recent evidence suggests differential involvement of opioid receptor subtypes in the anxiolytic efficacy of diverse compounds including conventional benzodiazepines. The insensitivity of 129 mice to the anxiolytic action of chlordiazepoxide, coupled with their atypical anxiolytic response to naloxone (but not more selective opioid receptor antagonists), suggests an abnormality in anxiety-related neurocircuitry involving opioid-GABA interactions.

The Role of Opioid Receptor Subtypes in the Development of Behavioral Sensitization to Ethanol

Nonspecific blockade of opioid receptors has been found to prevent development of behavioral sensitization to ethanol. Whether this effect is achieved through a specific opioid receptor subtype, however, is not clear. The present study investigated, for the first time, the role of specific opioid receptor subtypes in the development of ethanol-(2.5 g/kg/day; six sessions) induced locomotor sensitization in mice. We confirmed previous results showing that the nonspecific antagonism of opioid receptors (naltrexone; 0-2 mg/kg) prevented the development of behavioral sensitization to ethanol, an effect attained at doses presumed to occupy only mu opioid receptors. This was confirmed by using the selective mu opioid receptor antagonist CTOP (0-1.5 mg/kg), which also blocked sensitization to ethanol. The selective delta receptor antagonist, naltrindole (0-10 mg/kg), however, did not alter sensitization. We further assessed the role of mu opioid receptors in sensitization to ethanol by exploring the involvement of mu(1), mu(1+2), and mu(3) opioid receptor subtypes. Results of these experiments revealed that the blockade of mu(1) (naloxonazine; 0-30 mg/kg) or mu(3) opioid receptors (3-methoxynaltrexone; 0-6 mg/kg) did not prevent locomotor sensitization to ethanol. Using naloxonazine under treatment conditions that block mu(1+2) opioid receptor subtypes we observed a retarded sensitization. The present data suggest that the concurrent inactivation of all mu opioid receptor subtypes may be required to prevent the neural adaptations underlying the development of behavioral sensitization to ethanol. In addition, these results support previous data suggesting a putative role for the mu opioid receptor endogenous ligand, beta-endorphin, and the hypothalamic arcuate nucleus in ethanol sensitization.

Cocaine-like discriminative stimulus effects of heroin in squirrel monkeys: role of active metabolites and opioid receptor mechanisms.

Opioid agonists frequently have been reported to share discriminative stimulus (DS) effects with cocaine; however, the pharmacological basis of these shared effects is not understood completely. The present study assessed the ability of heroin and its deacetylated metabolites, 6-monoacetylmorphine (6-MAM) and morphine, to engender cocaine-like DS effects and investigated the role of opioid receptor subtypes in modulating these DS effects. Squirrel monkeys were trained to discriminate 0.3 mg/kg cocaine (i.m.) from vehicle under a 10-response fixed-ratio schedule of food reinforcement, and responding on the drug lever was assessed after varying i.m. doses of heroin, 6-MAM, and morphine. The potential role of opioid receptor mechanisms in modulating the cocaine-like DS effects of heroin and its metabolites was assessed with the mixed mu/kappa opioid antagonist naltrexone, the delta-selective antagonist naltrindole, and the kappa-selective antagonist nor-binaltorphimine. Heroin, 6-MAM, and morphine engendered dose-related increases in responding on the cocaine lever in three of four monkeys. Naltrexone shifted the dose-response functions for heroin and its metabolites to the right, and in vivo apparent pA2 analyses revealed that naltrexone antagonized the effects of the opioids in a manner consistent with mu receptor antagonism (apparent pA2 values ranging from 8.20 to 8.47). Naltrindole only minimally altered the dose-response functions of heroin, 6-MAM, and morphine, whereas nor-binaltorphimine did not block the cocaine-like DS effects of the three opioid agonists, suggesting that neither delta nor kappa receptors played a prominent role in the cocaine-like DS effects of heroin and its metabolites. These results suggest that heroin and its deacetylated metabolites engendered cocaine-like DS effects in a similar fashion. Furthermore, the cocaine-like DS effects of these opioids were modulated by a predominantly mu-opioid receptor mechanism.

Pharmacological characterization of buprenorphine, a mixed agonist–antagonist with κ3 analgesia

Buprenorphine is a mixed opioid agonist/antagonist analgesic. This study was designed to determine the role of opioid receptor subtypes, especially κ 3, in buprenorphine-induced analgesia in mice. Buprenorphine, when injected systemically, revealed a potent analgesic effect by tailflick assay, with a biphasic dose–response curve, which was reversed by naloxone. The presence of analgesic cross-tolerance between buprenorphine and naloxone benzoylhydrazone (NalBzoH) and morphine indicated a role for κ 3 and μ receptor subtype in buprenorphine analgesia. Additional studies with selective opioid antagonists indicated κ 1 mechanisms of action. We did not detect any involvement of the δ receptor subtype. Low doses of buprenorphine antagonized morphine analgesia, while high doses of buprenorphine coadministered with morphine elicited increasing analgesia in a dose-dependent manner. These findings suggest that buprenorphine elicits analgesia through an interaction with κ 3 receptors and to a lesser extent with κ 1 as well as its activity as partial μ receptor agonist.

Alcohol drinking is reduced by a μ1- but not by a δ-opioid receptor antagonist in alcohol-preferring rats

To assess the roles of opioid receptor subtypes in voluntary alcohol drinking, alcohol-preferring AA (Alko, Alcohol) rats, non-deprived of food or water, were used in a paradigm where access to 10% alcohol solution was limited to 1–4-h sessions on every 2nd working day. The δ-opioid receptor antagonist naltrindole (1–5 mg/kg i.p. 15 min before the session) had no effect on alcohol drinking, while it attenuated the δ-opioid receptor agonist [ d-Pen 2, d-Pen 5]enkephalin-induced locomotor stimulation. The μ 1-opioid receptor antagonist naloxonazine (1–15 mg/kg i.p. 20 h before the session), at the largest dose, decreased alcohol drinking. It also decreased food intake. When naltrindole (1 mg/kg) and naloxonazine (15 mg/kg) were given prior to 3 consecutive sessions, the former had no effects at any session. Naloxonazine decreased alcohol consumption only in the 1st session, although the reduction of daily water intake became stronger during repeated administration. 4 days after the last drug administration, naloxonazine-treated animals consumed alcohol nearly twice as much as in the control session before any drug treatment. These data suggest that δ-opioid receptors are not involved in the regulation of alcohol drinking in AA rats. μ 1-Opioid receptors may be involved in alcohol drinking, although the data suggest that even their prolonged blockade alone is insufficient to induce a sustained decrease in alcohol drinking.

MU- and Delta-opioid receptor-mediated epileptoid responses in morphine-dependent and non-dependent rats

In 3 different models of opioid epileptogenesis we have utilized opioid receptor antagonists to differentiate the nature and role of opioid receptor subtypes involved in opioid agonist-induced epileptoid responses in rats. Selective mu-opioid receptor agonism can initiate epileptoid responses in non-dependent rats. Delta-opioid agonism is important in sustaining mu-initiated epileptoid responses. A role for mu-opioid receptor stimulation in delta-opioid initiated epileptoid responses remains yet to be clarified. Delta-opioid antagonism does not precipitate classic autonomic and behavioral signs of withdrawal in morphine-dependent rats but blocks epileptoid responses in naloxone-precipitated morphine withdrawal without affecting automic and behavioral components of an ongoing withdrawal reaction.

The role of opioid receptor sub-types in tifluadom-induced feeding.

There is now considerable evidence that opioid agonists and benzodiazepines increase food and water intake in a variety of animal species. The appetitive effects of the novel opioid-benzodiazepine tifluadom have been investigated. (+/-)-Tifluadom significantly increased food intake in freely-feeding rats. This stimulation of appetite was attributable principally to the activity of the (+)-isomer. Furthermore tifluadom-induced feeding was blocked by the opioid antagonists naloxone, naltrexone, Mr 1452 and Mr 2266 but not by the delta-opioid receptor antagonist ICI 154, 129, or by the benzodiazepine antagonist Ro 15-1788. These results suggest that tifluadom exerts its effect on food intake by interaction with opioid as opposed to benzodiazepine receptors and that this activity is mediated by kappa and/or mu- rather than delta-opioid receptor sub-types.

Analgesic action and opioid receptor subtypes.

In order to study the roles of opioid receptor subtypes in the production of analgesia, analgesic potencies of relatively selective agonists for μ, δ and κ subtypes (morphine(MOR) to μ, [D-A]a2,D-Leu5]-enkephalin(DADL) to δ and ethylketocyclazocine(EKC) to κ) were examined with the tail-pinch test in S-D rats by microinjecting into the brain stem regions relevant to analgesia such as the nucleus reticularis paragigantocellularis(NRPG), nucleus raphe magnus(NRM) and periaqueductal gray(PAG), and lumbar subarachnoid space(LSS).