Jak1 inhibition reduces acute allodynia induced by specific upstream cytokines in rats: implications for the onset of Jak1 pain modulation

Clinical data from patients treated with Jak1 inhibitors for diverse autoimmune diseases point to a reduction of pain at the first readouts, hinting at an action on nociceptors prior to its immunomodulatory role. Dorsal root ganglion neurons have been shown to possess both receptors for cytokines that activate the Jak1 pathway, and Jak pathway enzymes. Cytokines that do or do not activate the Jak1 pathway and have receptors on nociceptors were administered intraplantarly to determine if these could induce a relatively quick mechanical allodynia in rats. Thus, IFNβ (300-600U), IFNα (300-600U), IL-1β (0.5-1 ng), TNFα (1-2.5 pg), and IL-6 (0.5-1 ng) evoked significant allodynia within 30 min of injection. IFNγ (1-10 ng) did not induce hind paw sensitivity. A Jak1 inhibitor, ABT-317 (1, 3, 10 mg/kg), administered 30 min prior to cytokine injection, prevented allodynia following IFNβ, IFNα, and IL-6 injections, but did not affect sensitivity after IL-1β or TNFα. The potent anti-inflammatory, prednisolone (10 mg/kg), did not affect the acute allodynia induced by IFNβ, IFNα, and IL-6 injections. ABT-317 (10 mg/kg) also reduced allodynia in a collagen arthritis model at a time when prednisolone was ineffective. ABT-317 did not modulate acute mechanical allodynia or nocifensive behaviors induced by prototypical nociceptor activators, AITC (500 µg) and capsaicin (10 µg). In addition to a well-accepted anti-inflammatory effect, the current data add to growing evidence suggesting a direct modulatory role for Jak1 inhibitors on nociceptors that can dampen pain signaling associated with specific cytokines like IL-6, IFNβ, and IFNα.