(S)-Nornicotine

(S)-Nornicotine is a nicotine metabolite that crosses the blood-brain barrier. (S)-Nornicotine weakly inhibits human CYP2A6 with a K_i >300 μM. (S)-Nornicotine promotes dopamine release in rat striatal and nucleus accumbens slices and increases endogenous DOPAC overflow through a calcium-dependent nAChR pathway that is sensitive to Mecamylamine (HY-B1395A). (S)-Nornicotine reduces behavioral responses maintained by nicotine or sucrose, exerts analgesic effects in persistent inflammatory pain and neuropathic pain models, and enhances the analgesic effect of morphine. (S)-Nornicotine is useful for research on tobacco dependence and pain^[1][2][3][4]. In Vitro:(S)-Nornicotine (0.1-100 μM) induces a concentration-dependent and sustained overflow of endogenous DOPAC in a rat striatal brain slice perfusion model, with no significant desensitization^[1].
(S)-Nornicotine (0.01-1.0 μM) does not modulate electrically stimulated overflow of endogenous DOPAC from superfused rat striatal slices^[1].
(S)-Nornicotine (0.1-100 μM) induces a concentration-dependent tritium overflow in the perfusate of rat striatal brain slices preloaded with [³H]DA, which is consistent with a direct stimulatory effect on dopamine release^[1].
(S)-Nornicotine (10-100 μM; 15 min) induces a calcium-dependent increase in endogenous DOPAC efflux in superfused rat striatal slices^[1].
(S)-Nornicotine (0.02-400 μM; 10 min) is a weak inhibitor of CYP2A6-mediated coumarin 7-hydroxylation expressed in human lymphoblastoid cells, with a K_i value ≥300 μM^[4]. In Vivo:(S)-Nornicotine (1-10 mg/kg; subcutaneous injection) dose-dependently reduces intravenous S (-)-nicotine self-administration behavior in rats^[2].
(S)-Nornicotine (1-10 mg/kg; s.c.) dose-dependently decreases sucrose-maintained responding in rats, with potency comparable to that of R (+)-nornicotine^[2].
(S)-Nornicotine (5.6-10 mg/kg; subcutaneous injection) dose-dependently reduces the duration of action of S (-)-nicotine self-administration^[2].
(S)-Nornicotine (3-5.6 mg/kg; subcutaneous injection; once daily; for 10 consecutive days) persistently reduces S (-)-nicotine self-administration behavior in rats over 10 days without producing tolerance^[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; single dose) reaches a mean brain concentration of 214.6 ng/mL in rats, and its brain exposure is similar to that of R (+)-nornicotine^[2].
(S)-Nornicotine (5.6 mg/kg; subcutaneous injection; once daily; for 9 consecutive days) causes sustained increases in blood pressure and heart rate in rats without producing tolerance^[2].
(S)-Nornicotine (0.5-20 mg/kg; i.p.; single dose) produces dose-dependent inhibition of formalin-induced flinching behavior in both phases of the rat formalin test, with similar potency in phase 1 and phase 2 (ED₅₀ approximately 1.5-1.8 mg/kg i.p.)^[3].
(S)-Nornicotine (10-40 mg/kg; i.p.) produces moderate dose-dependent antinociception in the acute thermal paw test in rats, with an i.p. ED₅₀ of 29.3 mg/kg^[3].
(S)-Nornicotine (2.5-20 mg/kg; i.p.) produces motor side effects at doses above those required for analgesia, with tactile allodynia showing the greatest dose separation^[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) does not exhibit significant antinociceptive activity in the rat tail-flick test^[3].
(S)-Nornicotine (2.5 mg/kg; 10-100 μg; i.p.; intrathecal injection) at sub-analgesic doses enhances the antinociceptive effect of morphine in the rat tail-flick test, and when administered intrathecally, the combination with morphine achieves approximately 100% of the maximum possible effect^[3].
(S)-Nornicotine (0.01-7.5 mg/kg; i.p.; p.o.) at subanalgesic doses enhances the antihyperalgesic effect of morphine in the rat CCI model, achieving 100% MPE at the combination dose without motor impairment as assessed by the rotarod test^[3].