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Background and Purpose: Opioid antagonists, such as naloxone and naltrexone, exhibit agonistic properties at the mutated μ receptor, MOR-S196ACSTA. In our previous study, systemic naloxone (10 mg·kg(-1) , s.c.) elicited antinociceptive effect without the induction of tolerance, dependence or rewarding effect in mice 2 weeks after intrathecal administration of double-stranded adeno-associated virus-MOR-S196ACSTA-eGFP. Here, we have investigated if this antinociceptive paradigm would be effective in a mouse model of neuropathic pain.Experimental Approach: Spinal nerves were ligated in male C57BL/6 mice 3 or 4 weeks after intrathecal injection of the lentivirus encoding the construct of MOR-S196ACSTA-eGFP (LV-MOR-S196ACSTA). Anti-allodynic effects of daily s.c.injections of saline, naltrexone (10 mg·kg(-1) ) or morphine (10 mg·kg(-1) ) were assessed by the von Frey test. After 14 days of treatment with saline, naltrexone or morphine, signs of natural withdrawal were measured at 22 and 46 h after the last injection. To determine the rewarding effects induced by morphine or naltrexone, the conditioned place preference test was carried out.Key Results: Anti-allodynic effects, as measured by von Frey test, increased after naltrexone or morphine treatment in mice transfected with LV-MOR-S196ACSTA in the spinal cord. Cessation of treatment with morphine, but not naltrexone, induced natural withdrawal and rewarding effects.Conclusions and Implications: Systemic injection of naltrexone after the expression of a mutant μ opioid receptor, MOR-S196ACSTA, in the spinal cord may have therapeutic potential for chronic neuropathic pain, without the development of dependence or addiction.Linked Articles: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. [ABSTRACT FROM AUTHOR]

In our previous study, we first demonstrated a significant effect of dextromethorphan (DM) on morphine-seeking behavior in morphine-dependent rats, when DM was given during morphine withdrawal. Using the same conditioned place preference (CPP) paradigm modified for measuring drug-seeking-related behavior, we further investigated the possible effect of DM on methamphetamine (MA)-seeking in MA-dependent rats. Our data showed that DM could also effectively suppress the drug-seeking behavior for MA, when administered during MA withdrawal. This suggests that DM may possess a pharmacological property to prevent drug-seeking behavior for addictive drugs in general. To examine the action sites of DM in the brain, DM was microinjected into the VTA or the NAc, and tested for its effect on MA-seeking during withdrawal. Both intra-VTA and intra-NAc injections of DM were able to block the MA-seeking, suggesting that DM has a dual action sites. In our neurochemical results, intra-NAc injection of DM showed a clear reduction of DA turnover rate at the NAc and the mPFC in response to MA challenge during withdrawal, which matched with the behavioral results. However, intra-VTA injection of DM reduced the DA turnover rate at the mPFC but did not have effect on the DA turnover rate at the NAc. Although further investigations may be needed to verify the connection between our neurochemical and behavioral results, the present study highlights the therapeutic potential of DM in antidrug-seeking behavior of MA and that the mechanism could be related to its effect on the mesolimbic and mesocortical dopaminergic pathways. Synapse 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Midbrain periaqueductal gray (PAG) and spinal cord dorsal horn are major action sites of opioid analgesics in the pain pathway. Our previous study has shown that opioid antagonists activate MORS196A-CSTA (a mutant of mu-opioid receptor) as full agonists in vitro cell models and naloxone showed antinociceptive effects after the expression of MORS196A-CSTA in the spinal cord in mice. The purpose of this study is to investigate the site-directed antinociceptive effects of naloxone in mice injected with dsAAV-MORS196A-CSTA-EGFP at spinal cord or at periaqueductal gray. MORS196A-CSTA-EGFP was administered to ICR mice using dsAAV as vector. We measured MORS196A-CSTA-EGFP expression by detecting the EGFP visualization with a fluorescence microscope. The antinociceptive effect of naloxone was determined by tail-flick test and hot plate test. Drug rewarding effect was evaluated by the conditioned place preference test. Naloxone (10 mg/kg, s.c.) elicited both supraspinal and spinal antinociceptive responses in mice injected with the virus at PAG while only spinal antinociceptive response was observed in mice injected with virus at dorsal horn region. Chronic naloxone treatment did not induce physical dependence or rewarding effect in mice injected with MORS196A-CSTA-EGFP in spinal cord or PAG. These data suggest that the observed naloxone-induced antinociceptive response is the consequence of the local expression of MORS196A-CSTA at specific sites of pain pathway. Injection of such MOR mutant and the systemic administration of naloxone can be a new strategy in the management of chronic pain without the various side effects associated with the use of morphine. Synapse, 2012. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Previously we showed that coadministration of dextromethorphan (DM) with morphine attenuates morphine-rewarding effect. Here we further investigated if DM is effective in reversing or treating drug-seeking effect when given after subchronic morphine treatment. The conditioned place preference (CPP) test was used to investigate the rewarding and drug-seeking effects of morphine. Rats were injected and conditioned with morphine for 6 days and then withdrawn from morphine for 4 days and treated with saline or DM during this period. Subchronic morphine induced a significant place preference for the drug-paired compartment. DM treatment during the morphine withdrawal period significantly reversed the preference from the drug-paired compartment to saline-paired compartment. Both nucleus accumbens (NAc) and VTA were proven to be the sites involved in the action of DM. Behavioral sensitization occurred in both morphine group and DM treatment group determined by the locomotor activity before and after subchronic morphine treatment. The dopamine (DA) turnover rate in the NAc, dorsal striatum (DS) and medial prefrontal cortex (mPFC) was increased after subchronic morphine treatment. DM treatment reversed the increase of DA turnover rate in the NAc but not in the DS or mPFC. These data suggest that DM might have potential in the treatment of morphine addiction. Synapse 61:420-428, 2007. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Infants passively exposed to morphine or heroin through their addicted mothers usually develop characteristic withdrawal syndrome of morphine after birth. In such early life, the central nervous system exhibits significant plasticity and can be altered by various prenatal influences, including prenatal morphine exposure. Here we studied the effects of prenatal morphine exposure on postsynaptic density protein 95 (PSD-95), an important cytoskeletal specialization involved in the anchoring of the NMDAR and neuronal nitric oxide synthase ( nNOS), of the hippocampal CA1 subregion from young offspring at postnatal day 14 (P14). We also evaluated the therapeutic efficacy of dextromethorphan, a widely used antitussive drug with noncompetitive antagonistic effects on NMDARs, for such offspring. The results revealed that prenatal morphine exposure caused a maximal decrease in PSD-95 expression at P14 followed by an age-dependent improvement. In addition, prenatal morphine exposure reduced not only the expression of nNOS and the phosphorylation of cAMP responsive element-binding protein at serine 133 (CREBSerine-133), but also the magnitude of long-term depression (LTD) at P14. Subsequently, the morphine-treated offspring exhibited impaired performance in long-term learning and memory at later ages (P28-29). Prenatal coadministration of dextromethorphan with morphine during pregnancy and throughout lactation could significantly attenuate the adverse effects as described above. Collectively, the study demonstrates that maternal exposure to morphine decreases the magnitude of PSD-95, nNOS, the phosphorylation of CREBSerine-133, and LTD expression in hippocampal CA1 subregion of young offspring (e.g., P14). Such alterations within the developing brain may play a role for subsequent neurological impairments (e.g., impaired performance of long-term learning and memory). The results raise a possibility that postsynaptic density proteins could serve an important role, at least in part, for the neurobiological pathogenesis in offspring from the morphine-addicted mother and provide tentative therapeutic strategy. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) exhibits remarkable plasticity in early life and can be altered significantly by various prenatal influences. We previously showed that prenatal exposure to morphine altered kinetic properties of N-methyl- D-aspartate (NMDA) receptor-mediated synaptic currents in the hippocampus of young rat offspring at the age of 14 days (P14). The present study further investigates whether NMDA receptor-mediated synaptic plasticity and/or cyclic adenosine monophosphate-responsive element-binding protein (CREBSerine-133), an important transcription factor underlying learning and memory, can be altered by prenatal morphine exposure in these offspring. Subsequently, the Morris water maze task was performed at the older ages (P28-P31). The magnitude of long-term depression (LTD) generated by a low-frequency stimulation (LFS, 1 Hz for 15 min) in hippocampal slices from the vehicle-control offspring (P14) was significantly larger than that in slices from the morphine-treated offspring, although there was no such difference in the magnitude of long-term potentiation (LTP) elicited by a high-frequency stimulation (100 Hz for 1 s) between the two groups. Comparison of the expression range of glutamatergic synaptic plasticity in slices from the vehicle-control and morphine-treated offspring, calculated as the difference in the maximal magnitude between LTP and LTD, demonstrated a remarkably smaller range in the slices from the morphine-treated offspring. In addition, the decreased phosphorylation of CREBSerine-133 and the impaired ability of spatial learning were also seen in the morphine-treated offspring, as compared with the vehicle-control offspring. Collectively, the study suggests that maternal exposure to morphine reduces the range of synaptic plasticity by decreasing the expression of LTD, but not of LTP, in CA1 pyramidal neurons of the hippocampus from rat offspring. More importantly, decreased phosphorylation of CREBSerine-133 may play a role for the impaired spatial learning and memory in rat offspring exposure to prenatal morphine. Thus, the findings here may provide important insights into cellular/molecular mechanisms underlying pathophysiological changes in the CNS of young offspring from morphine-addicted mothers and serve as a basis for possible therapeutic intervention. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]