Pharmacological effects of nonselective and subtype-selective nicotinic acetylcholine receptor agonists in animal models of persistent pain

Abstract

Nicotinic acetylcholine receptors (nAChRs) are longstanding targets for a next generation of pain therapeutics, but the nAChR subtypes that govern analgesia remain unknown. We tested a series of nicotinic agonists, including many molecules used or tried clinically, on a panel of cloned neuronal nAChRs for potency and selectivity using patch-clamp electrophysiology and a live cell-based fluorescence assay. Nonselective nicotinic agonists as well as compounds selective either for alpha4beta2 or for alpha7 nAChRs were then tested in the formalin and complete Freund's adjuvant models of pain. Nonselective nAChR agonists ABT-594 and varenicline were effective analgesics. By contrast, the selective alpha4beta2 agonist ispronicline and a novel alpha4beta2-selective potentiator did not appear to produce analgesia in either model. alpha7-selective agonists reduced the pain-related endpoint, but the effect could be ascribed to nonspecific reduction of movement rather than to analgesia. Neither selective nor nonselective alpha7 nicotinic agonists affected the release of pro-inflammatory cytokines in response to antigen challenge. Electrophysiological recordings from spinal cord slice showed a strong nicotine-induced increase in inhibitory synaptic transmission that was mediated partially by alpha4beta2 and only minimally by alpha7 subtypes. Taken with previous studies, the results suggest that agonism of alpha4beta2 nAChRs is necessary but not sufficient to produce analgesia, and that the spinal cord is a key site where the molecular action of nAChRs produces analgesia.

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

“…7). The potency of both drugs in the mouse formalin test was higher than the one reported in the rat formalin model (Cucchiaro et al, 2008;Gao et al, 2010), suggesting possible species differences in drug pharmacokinetics and/or dynamics. Although both partial agonists were active in the formalin test, their antinociceptive effects were mediated by different nAChR subtypes as shown by the use of various nicotinic antagonists and nicotinic KO mice.…”

“…In contrast, varenicline and sazetidine-A both were reported to be possess antinociceptive activity in tonic pain models such as the formalin test in rodents (Cucchiaro et al, 2008;Gao et al, 2010). However, despite the in vitro binding data indicating that varenicline and sazetidine-A have higher affinity than nicotine to ␣4␤2* nAChRs (more than 10-fold), they possessed lower potencies and efficacies than nicotine in the formalin test (Cucchiaro et al, 2008;Gao et al, 2010). It is unclear whether these in vivo discrepancies are the result of differences in receptor efficacy and/or desensitization at various nAChR subtypes.…”

Intrathecal α-conotoxins Vc1.1, AuIB and MII acting on distinct nicotinic receptor subtypes reverse signs of neuropathic pain

“…7 (Gao et al 2010) and perhaps 3 subunit-containing (Takeda et al 2003;Gao et al 2010) nAChRs have also been proposed to make a small contribution to nicotinic excitation of dorsal horn GABAergic interneurons. We have previously shown that Vc1.1 is anti-allodynic in neuropathic pain models when administered intramuscularly, and that sustained reversal of allodynia appears due to GABA B -receptor-dependent inhibition of Ntype Ca 2+ channels because it is reversed by a selective GABA B -receptor antagonist (Klimis et al 2011).…”

The Antinociceptive Effects of Nicotinic Receptors α7-Positive Allosteric Modulators in Murine Acute and Tonic Pain Models

“…Furthermore, a7 nAChR agonists, such as choline, CDP-choline, compound B, JN403 [(S)-(1-azabicyclo [2.2.2]oct-3-yl)-carbamic acid (S)-1-(2-fluoro-phenyl)-ethyl ester], and (2)-spiro[1-azabicyclo[2.2.2]octane-3,59-oxazolidin]-29-one (AR-R17779, exhibited anti-inflammatory effects in various inflammation and pain models in rodents (Damaj et al, 2000;Medhurst et al, 2008;Feuerbach et al, 2009;Gurun et al, 2009;van Maanen et al, 2009;Rowley et al, 2010;Marrero et al, 2011;Munro et al, 2012). Although a7 nAChR agonists showed beneficial effects in inflammatory animal models in some studies, these effects were not seen consistently in other studies (Gao et al, 2010). Furthermore, subchronic treatment with such compounds may provide suboptimal therapeutic efficacy because of sustained activation and/or desensitization of the a7 nAChRs.…”