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 ∼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 ^V1.1, Na ^V1.3, Na ^V1.7-Na ^V1.9, Ca ^V2.2, and Ca ^V3.2. Numerous Na ^Vand Ca ^Vmodulators 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 ^Vand Ca ^V3 channels. Tap1a and Tap2a inhibited on-Target Na ^Vand Ca ^V3 channels at nanomolar to micromolar concentrations and displayed moderate off-Target selectivity for Na ^V1.6 and weak affinity for Na ^V1.4 and Na ^V1.5. 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 ^Vand Ca ^V3 subtypes provides a novel route for treatment of chronic visceral pain.