u-50488 and nalmefene

Cocaine addiction treatment is difficult due to the current lack of approved pharmacotherapuetics. Several preclinical and clinical studies have demonstrated that the mu opioid receptor (MOPr) antagonist/kappa opioid receptor (KOPr) partial agonist naltrexone (NTX) reduces the subjective effects and self-administration of cocaine. However, very limited research has examined the ability of the structurally similar MOPr antagonist/KOPr partial agonist nalmefene (NMF) to reduce cocaine reward. Here we examine the effect of low (1 mg/kg) and high (10 mg/kg) doses of NTX or NMF on cocaine place preference. In vivo characterization of these NTX and NMF doses were performed to examine their effectiveness at MOPr and KOPr.. Both NTX doses and high dose NMF significantly reduced cocaine place preference. Conversely, a significant place avoidance was observed for high dose NTX and both NMF doses. Interestingly, neither NTX nor NMF blocked cocaine-induced hyperlocomotion. High dose NTX and both NMF doses fully blocked MOPr agonist morphine-induced thermal analgesia as well as KOPr agonist U50,488H-induced locomotor discoordination. However, low dose NTX fully blocked morphine analgesia but not U50,488H locomotor discoordination suggesting that low dose NTX is effective at MOPr but not KOPr.. Both NTX and NMF block the place preference, but not locomotor activating, effects of cocaine. These results suggest that both NTX and NMF may be viable pharmacotheraputics for some aspects of cocaine addiction. This is an important step to understanding the potential mechanism(s) of action of NTX and NMF for the development of more efficacious pharmacological treatments for substance use disorders.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesia; Analgesics, Opioid; Animals; Cocaine; Conditioning, Psychological; Dose-Response Relationship, Drug; Locomotion; Male; Mice; Morphine; Naltrexone; Narcotic Antagonists

Kappa(kappa) opioid agonists slow gastrointestinal transit in the guinea pig and the mouse but not the rat. Opioid antagonists naloxone and naltrexone are mu (mu) preferring, while the antagonist nalmefene has more kappa binding activity. When administered orally, the specific opioid antagonists naloxone, naltrexone, and nalmefene are able to reverse the gastrointestinal transit delay caused by orally administered mu and kappa opioid agonists (morphine and U-50, 488H) in a dose dependent fashion as measured by the leading edge of charcoal meal in the guinea pig. Oral naltrexone and nalmefene have significantly more central nervous system (CNS) bioavailability than oral naloxone. However, orally administered naloxone was as effective as either naltrexone or nalmefene in reversing mu opioid agonist induced orocecal transit delays (single agonist dose apparent ED50s = 12.3 +/- 4, 7.3 +/- 4, and 13.5 +/- 6 mg/kg respectively). Nalmefene was more active than either naltrexone or naloxone in its ability to reverse the kappa agonist U-50,488H (single agonist dose apparent ED50s = 18.3 +/- 12*, 37.5 +/- 5, and 61.9 +/- 5 mg/kg respectively; * = p < 0.05). These data confirm the enteric action of orally administered opioids and further supports our earlier findings of the presence of kappa opioid activity in the guinea pig enteric nervous system.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Gastrointestinal Transit; Guinea Pigs; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Pyrrolidines; Receptors, Opioid, kappa; Receptors, Opioid, mu

A reproducible spinal cord injury model was used to compare the efficacy of three compounds previously shown to improve neurologic recovery after injury in rats: The thyrotropin releasing hormone (TRH) analogue, YM-14673; the specific kappa-opioid agonist, U-50488H; and the opioid antagonist, nalmefene, which has increased activity at kappa-receptors. A moderate injury in rats that results in recovery of uncoordinated gross locomotion was made at spinal T9 by rapid displacement (1.1. mm) of the cord. Compounds (or vehicle) were given either by intravenous bolus or by continuous mini-osmotic pump over 7 days, beginning 30 min after the injury as follows: controls (saline), YM-14673 (1 mg/kg bolus), U-50488H (10 mg/kg bolus), U-50488H (0.425 mg/kg/h continuous infusion x 7 days); nalmefene (0.1 mg/kg bolus); and nalmefene (0.021 mg/kg/h continuous infusion x 7 days). Neurologic recovery was assessed for 4 weeks by open-field walking, inclined plane, grid walking, and footprint analysis. The percentage of white matter spared was determined at the lesion epicenter. Only those groups given a bolus of YM14673, U-50488H, and nalmefene had open-field performance better than the scores of controls. Animals that received a bolus of YM-14673 also scored better than controls on the inclined plane and were more likely than controls to recover sufficiently to be tested by both grid walking and footprint analysis. Improved behavioral recovery was not found in groups that received chronic drug infusion. Histology demonstrated significant sparing of white matter for the YM-14673-treated group compared with controls; groups given a U-50488H and nalmefene bolus showed a trend for greater sparing of white matter. The results confirm a beneficial effect for these compounds and suggest that they may be useful in treatment of clinical spinal cord injury.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Azetidines; Dipeptides; Female; Naltrexone; Narcotic Antagonists; Nervous System; Pyrrolidines; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries