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-methylnaloxone 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-methylnaloxone 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 −1s.c.) significantly reduced the jumping latencies 2h 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 intrepreting the effects after quaternary derivatives of opioid antagonists.
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