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

Abstract Chronic pain is a serious debilitating condition that affects ∼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.