title: Effects of N-methylnaloxone and N-methylnaltrexone on nociception and precipitated abstinence in mice.
abstract: Subcutaneous administrations of naloxone and naltrexone have already been shown to enhance nociceptive reactions in mice. The present study was undertaken to examine the effects of N-methyl-naloxone and N-methylnaltrexone on nociception using the hot plate test (dose range: 0.3 to 30 mg kg-1s.c.). The latter compounds were selected to differentiate the central and peripheral components of hyperalgesia. Unlike naloxone, N-methyl-naloxone did not produce hyperalgesia. Similarly low doses of N-methylnaltrexone did not enhance the jumping response. However, a high dose of N-methylnaltrexone (30 mg kg-1 s.c.) significantly reduced the jumping latencies 2 h after its administration. This phenomenon indicated that it might be converted to an active metabolite. Further, N-methylnaloxone and N-methylnaltrexone were very weak in precipitating the signs of abstinence in mice rendered acutely dependent on morphine. Two factors, poorer penetration into the CNS and steric hindrance, might render the N-methylated antagonists weak. Hence, both these factors should be considered when interpreting the effects after quaternary derivatives of opioid antagonists.
mesh_terms: D000818:Animals; D006801:Humans; D004091:Hydromorphone / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D009021:Morphine Dependence / Q000188:drug therapy; D009270:Naloxone / Q000031:analogs & derivatives*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D010111:Oxymorphone / Q000627:therapeutic use*; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D000644:Quaternary Ammonium Compounds; D012684:Sensory Thresholds
chemical_list: D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; C032257:methylnaltrexone; D009270:Naloxone; D009271:Naltrexone; D010111:Oxymorphone; D004091:Hydromorphone