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.