A Selective Adenylyl Cyclase 1 Inhibitor Relieves Pain Without Causing Tolerance

Abstract

Among the ten different adenylyl cyclase isoforms, studies with knockout animals indicate that inhibition of AC1 can relieve pain and reduce behaviors linked to opioid dependence. We previously identified ST034307 as a selective inhibitor of AC1. The development of an AC1-selective inhibitor now provides the opportunity to further study the therapeutic potential of inhibiting this protein in pre-clinical animal models of pain and related adverse reactions. In the present study we have shown that ST034307 relives pain in mouse models of formalin-induced inflammatory pain, acid-induced visceral pain, and acid-depressed nesting. In addition, ST034307 did not cause analgesic tolerance after chronic dosing. We were unable to detect ST034307 in mouse brain following subcutaneous injections but showed a significant reduction in cAMP concentration in dorsal root ganglia of the animals. Considering the unprecedented selectivity of ST034307, we also report the predicted molecular interaction between ST034307 and AC1. Our results indicate that AC1 inhibitors represent a promising new class of analgesic agents that treat pain and do not result in tolerance or cause disruption of normal behavior in mice. In addition, we outline a unique binding site for ST034307 at the interface of the enzyme’s catalytic domain.

Exaptation and Evolutionary Adaptation in Nociceptor Mechanisms Driving Persistent Pain

“…In mammalian nociceptors, more is known about AC5/6 (see below) than AC1, and mRNA for AC5 and AC6 is more highly expressed than mRNA for AC1 both in rat DRGs [80] and in most rodent and primate nociceptors [173, 174]. However, indirect evidence suggests a contribution of nociceptor AC1 to sensitization in mice [175]. This could be explained by contributions from the relatively small population of myelinated Aδ nociceptors, which express more AC1 than do nociceptors in unmyelinated C-fiber subpopulations in mammals [173, 174], and which display striking similarities to Aplysia nociceptors in rapid axonal conduction relative to other nociceptor types in the same species, large receptive fields, sensitivity to a wide range of intensities of mechanical stimuli, and sensitization of mechanosensory responses by noxious mechanical stimulation [35, 65, 176].…”