A spider-venom peptide with multitarget activity on sodium and calcium channels alleviates chronic visceral pain in a model of irritable bowel syndrome

Chronic pain is a serious debilitating condition that affects similar to 20% of the world's population. Currently available drugs fail to produce effective pain relief in many patients and have dose-limiting side effects. Several voltage-gated sodium (Na-v) and calcium (Ca-v) channels are implicated in the etiology of chronic pain, particularly Na(v)1 .1, Na(v)1 .3, Na(v)1 .7-Na(v)1 .9, Ca(v)2.2, and Ca(v)3.2. Numerous Na-v and Ca-v modulators have been described, but with few exceptions, they display poor potency and/or selectivity for pain-related channel subtypes. Here, we report the discovery and characterization of 2 novel tarantula-venom peptides (Tap1a and Tap2a) isolated from Theraphosa apophysis venom that modulate the activity of both Na-v and Ca(v)3 channels. Tap1a and Tap2a inhibited on-target Na-v and Ca(v)3 channels at nanomolar to micromolar concentrations and displayed moderate off-target selectivity for Na(v)1 .6 and weak affinity for Na(v)1 .4 and Na(v)1 .5. The most potent inhibitor, Tap1a, nearly ablated neuronal mechanosensitivity in afferent fibers innervating the colon and the bladder, with in vivo intracolonic administration reversing colonic mechanical hypersensitivity in a mouse model of irritable bowel syndrome. These findings suggest that targeting a specific combination of Na-v and Ca(v)3 subtypes provides a novel route for treatment of chronic visceral pain.