DOSE-DEPENDENT ANTAGONISM AND POTENTIATION OF NITROUS-OXIDE ANTINOCICEPTION BY NALOXONE IN MICE

Administration of the anesthetic gas nitrous oxide (N2O evoked a conce ntration-dependent antinociceptive effect in mice as assessed by the a bdominal constriction test. Depending on the dose and route of pretrea tment with the opioid receptor blocker naloxone, the N2O drug effect w as either antagonized or potentiated. After s.c. pretreatment with mil ligram per kilogram doses of naloxone, dose-related antagonism occurre d; picogram per kilogram doses potentiated N2O-induced antinociception . The i.c.v. pretreatment with microgram quantities of naloxone also a ntagonized N2O antinociception in a dose-related fashion; i.c.v. pretr eatment with femtogram doses was without effect. On the other hand, in trathecal (i.t.) pretreatment with femtogram quantities of naloxone po tentiated N2O antinociception: i.t. pretreatment with microgram quanti ties continued to antagonize the antinociceptive effect. The same patt ern of interaction was observed in mice challenged with the kappa opio id analgesic drug trans -dichlow-N-methyl-N-[2-(1-pyrrolidinyl)cyclohe xyl] benzeneacetamide methane sulfonate (U-50, 488H) after s.c., i.c.v . or i.t. pretreatments with high and low doses of naloxone. These res ults 1) demonstrate further similarities in the opioid receptor mediat ion of N2O and U-50, 488H antinociceptive effects and also 2) support the concept of high-affinity spinal opioid receptors, whose blockade b y s.c.- or i.t.- but not i.c.v.-administered low-dose naloxone can pot entiate the antinociceptive effects of both N2O and U-50,488H. These f indings suggest that the antinociceptive effect of N2O might be modula ted by a descending opioid system that inhibits analgesia.