sazetidine-a and Pain

Nicotinic agonists display a wide-range profile of antinociceptive activity in acute, tonic, and chronic pain models. However, their effectiveness is limited by their unacceptable side effects. We investigated the antinociceptive effects of two new α4β2* nicotinic partial agonists, varenicline and sazetidine-A, in acute thermal and tonic pain mouse models. Both drugs failed to induce significant effects in the tail-flick and hot-plate tests after subcutaneous administration. However, they blocked nicotine's effects in these tests at very low doses. In contrast to acute pain tests, varenicline and sazetidine-A dose-dependently induced an analgesic effect in the mouse formalin test after systemic administration. Their antinociceptive effects were mediated, however, by different nicotinic acetylcholine receptor (nAChR) subtypes. Sazetidine-A effects were mediated by β2* nAChR subtypes, whereas varenicline actions were attributed to α3β4 nAChRs. Moreover, low inactive doses of varenicline blocked nicotine's actions in phase II of the formalin test. Overall, our results suggest that the antagonistic actions of varenicline at low doses are mediated by β2*-nAChRs and at higher doses as an agonist by α3β4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by β2*-nAChR subtypes. These results suggest that nicotinic partial agonists possess analgesic effects in a rodent tonic pain model and may provide a potential treatment for the treatment of chronic pain disorders.

Topics: Analgesics; Animals; Azetidines; Benzazepines; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Motor Activity; Nicotinic Agonists; Pain; Pain Measurement; Pyridines; Quinoxalines; Receptors, Nicotinic; Varenicline

The use of nicotinic agonists for analgesia is limited by their unacceptable side effects. Sazetidine-A is a new partial agonist nicotinic ligand that has very high selectivity for beta2-containing nicotinic acetylcholine receptors. It potently and selectively desensitizes alpha4beta2 nicotinic acetylcholine receptors without measurable effects on alpha3beta4 receptors. The authors investigated the analgesic effects of Sazetidine-A using the formalin model of chronic inflammatory pain.. The formalin test was conducted after rats received intraperitoneal saline, Sazetidine-A (0.125, 0.25, 0.5, 1, 2 mg/kg), or subcutaneous epibatidine (2.5-5-10 mug/kg). In other experiments, Sazetidine-A was preceded by naloxone (0.5 mg/kg) or mecamylamine (10 mg). Effects of Sazetidine-A and epibatidine on locomotor were tested in an open field, and seizure activity was measured using the Racine scale. Locus coeruleus neuron extracellular single-unit spontaneous discharge was recorded in anesthetized animals after Sazetidine-A and epibatidine.. Higher doses of Sazetidine-A (0.5, 1, or 2 mg/kg) induced analgesia, with pain scores significantly lower than those seen after saline, lower doses of Sazetidine-A, and epibatidine (P < 0.001). Naloxone did not antagonize the effects of Sazetidine-A, and mecamylamine had partial, dose-dependent antagonistic effects. Epibatidine excited locus coeruleus neurons, whereas Sazetidine-A had no effect on these neurons. Epibatidine and Sazetidine-A affected animals' locomotor activity for the initial 20 min. While analgesic doses of epibatidine caused seizures, no seizure activity or other neurologic complications were seen in animals that received as much as four times the minimum analgesic dose of Sazetidine-A.. Sazetidine-A seems to be a potent analgesic without causing neurologic side effects.

Topics: Analgesics; Animals; Azetidines; Bridged Bicyclo Compounds, Heterocyclic; Cholinergic Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mecamylamine; Motor Activity; Naloxone; Narcotic Antagonists; Nicotinic Agonists; Nicotinic Antagonists; Pain; Pain Measurement; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Nicotinic; Sodium Chloride