TIMP-1 as a Potential Effector of Ion Channel Expression and Inflammatory Pain

Millions of Americans are affected by chronic pain, yet treatment remains largely ineffective. Unresolved inflammation contributes to chronic pain development and understanding how inflammation resolves is integral for developing effective therapeutics. Towards this goal, we have identified tissue inhibitor of metalloproteinases (TIMP-1) as a regulator of inflammatory pain. Mice with genetic deletions of TIMP-1 (T1KO) exhibit prolonged mechanical and thermal hypersensitivity following cutaneous inflammation compared to wild-type (WT) mice. Electrophysiological recordings from nociceptive neurons revealed that T1KO nociceptors exhibit lower activation thresholds and increased incidence of spontaneous activity and after discharge in response to inflammation. These results suggest that increased nociceptor firing increases behavioral sensitivity in T1KO mice. Recent RNA sequencing of the dorsal root ganglia (DRG) has identified multiple high priority transcriptomic targets that may underlie nociceptor responsiveness in T1KO mice, including increased expression of Scn9a (Nav1.7), Scn10a (Nav1.8), Trpm3, and Piezo2, which all encode ion channels in neurons that either sense or propagate noxious stimuli. Subsequent analysis of protein and gene expression confirm increased expression of Nav1.7 in T1KO DRG, suggesting that TIMP-1 may serve to normalize Nav-dependent nociceptor action potential firing. Inhibition of one of these channels alone is insufficient to significantly reduce the multimodal aspects associated with pathological pain states, illustrating the critical need to develop intervention strategies designed to simultaneously modulate activity of multiple targets. These results suggest a novel TIMP-1-mediated mechanism that may function to attenuate inflammatory pain. NINDS R03NS096454, NINDS R21NS104789 (KMB) Rita Allen Foundation Award in Pain (KMB) KUMC Biomedical Research Training Program (OCE) Madison and Lila Self Graduate Fellowship (RNS) NIGMS P20GM103418 (KMB, OCE, EEY).