Analgesia induced by chronic nicotine infusion in rats - Differences by gender and pain test

Rationale: Acute administration of nicotine induces analgesia with subseque nt development of tolerance. In human studies, females are less sensitive t o the analgesic effects of nicotine than males. Few previous animal studies have investigated analgesic effects of chronic nicotine administration or addressed gender differences. Objectives: To investigate whether chronic ad ministration of nicotine induces analgesia in male and female rats as asses sed by a battery of standard pain assays, if tolerance develops, and if hyp eralgesia occurs following cessation of nicotine. Methods: Nicotine (free b ase; 6 mg/kg/day i.v.) or saline was administered for 2 weeks via implanted osmotic pumps. Pain behavior was assessed before, during, and for 3 weeks after nicotine infusion by measuring tail flick latency, hot-plate latency, and thermal paw withdrawal latency. The paw-withdrawal threshold to non-no xious mechanical stimuli was also measured. Effects of nicotine infusion, g ender, and time were assessed by three-way analyses of variance. Results: B oth male and female rats exhibited a comparable degree of analgesia in the hot-plate test with development of tolerance during the 2-week infusion per iod. Males, but not females, showed analgesia in the tail flick test. Analg esia was not observed for thermally evoked paw withdrawal in either males o r females, nor did nicotine affect non-noxious mechanically evoked paw with drawals. Males and females showed cessation of weight gain during the first week of nicotine infusion. Conclusions: Chronic nicotine-induced analgesia was confirmed in both male and female rats as assessed using the hot-plate test which reflects integrated pain behavior. Males, but not females, exhi bited analgesia in a nociceptive withdrawal reflex test (tail flick), indic ating that nicotine-induced analgesia may depend on both the type of pain t est and gender. The lack of nicotine-induced analgesia assessed by the tail flick reflex test in female rats is consistent with recent human studies s howing that nicotine reduces pain elicited by brief noxious cutaneous stimu lation in male but not female subjects.