The Antinociceptive Effects of Nicotinic Partial Agonists Varenicline and Sazetidine-A in Murine Acute and Tonic Pain Models

Abstract

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 ␣4␤2* 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 ␤2* nAChR subtypes, whereas varenicline actions were attributed to ␣3␤4 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 ␤2*-nAChRs and at higher doses as an agonist by ␣3␤4*-nAChRs. In contrast, both actions of sazetidine-A are mediated by ␤2*-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.

The role of alpha5 nicotinic acetylcholine receptors in mouse models of chronic inflammatory and neuropathic pain

“…Our results showed that the nicotine and sazetidine anti-nociceptive effects were fully dependent on α 5 subunits in both phases I and II of the formalin test. These results along with our recent report [16], suggest that the antinociceptive effects of nicotine and sazetidine-A in the formalin test appears to be mediated largely by α 4 α 5 β 2 *-nAChRs subtypes. In contrast, α 5 *-nAChRs subtypes do not mediate the effects of varenicline in the same test.…”

“…These active doses were selected based on our recent report in the same test [16]. All behavioral testing on WT and KO animals in this study was performed in a blinded manner.…”

Chemistry and Pharmacological Studies of 3-Alkoxy-2,5-Disubstituted-Pyridinyl Compounds as Novel Selective α4β2 Nicotinic Acetylcholine Receptor Ligands That Reduce Alcohol Intake in Rats

“…47-50, 52, 63-69 The results from these studies are highly supportive of our proposal to develop novel nicotinic therapeutics based on their ability to selectively desensitize α4β2 nA-ChRs. In the present study, we investigated the agonist and desensitization properties of these new analogs at human α4β2 nAChRs and rat α3β4 nAChRs (Table 2).…”

Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system

“…In studies using nAChR agonists and antagonists as well as mice with nAChR subunits null mutations, researchers have shown that nAChRs containing α3, α4, α5, α6, α7, β2, and β4 subunits are involved in modulating nocifensive behaviors in response to acute noxious thermal stimuli (Damaj et al, 2007; Damaj et al, 1999; Marubio et al, 1999) and in response to inflammatory and neuropathic processes (AlSharari et al, 2012; Bagdas et al, 2015; Damaj et al, 1999; Freitas et al, 2015; Saika et al, 2015; Wieskopf et al, 2015; Xanthos et al, 2015; Yalcin et al, 2011). Others have also shown that mice with null mutations of α4, α5, or β2 have decreased response to the analgesic effects of nicotine, but intact response to the antinociceptive effects of morphine (Damaj et al, 2007; Marubio et al, 1999).…”