Effects of N-methylnaloxone and N-methylnaltrexone on nociception and precipitated abstinence in mice.

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.