Cortistatin attenuates inflammatory pain via spinal and peripheral actions

Abstract

Clinical pain, as a consequence of inflammation or injury of peripheral organs (inflammatory pain) or nerve in jury (neuropathic pain), represents a serious public health issue. Treatment of pain-related suffering requires knowledge of how pain signals are initially interpreted and subsequently transmitted and perpetuated. To limit duration and intensity of pain, inhibitory signals participate in pain perception. Cortistatin is a cyclic neuropeptide that exerts potent inhibitory actions on cortical neurons and immune cells. Here, we found that cortistatin is a natural analgesic component of the peripheral nociceptive system produced by peptidergic noci ceptive neuronsofthedorsalrootgangliainresponsetoinflammatoryandnoxiousstimuli.Moreover,cortistatin is produced byGABAergicinterneurons of deeplayers of dorsalhornofspinalcord. Byusing cortistatin-deficient mice, we demonstrated that endogenous cortistatin critically tunes pain perception in physiological and patho logical states. Furthermore, peripheral and spinal injection of cortistatin potently reduced nocifensive behavior, heat hyperalgesia and tactile allodynia in experimental models of clinical pain evoked by chronic inflammation, surgery and arthritis. The analgesic effects of cortistatin were independent of its anti-inflammatory activity and directly exertedonperipheralandcentralnociceptiveterminalsviaGαi-coupledsomatostatin-receptors(mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including protein kinase A-, calcium andAkt/ERK-mediatedreleaseofnociceptivepeptides.Moreover,cortistatincouldmodulate,throughitsbinding to ghrelin-receptor (GHSR1), pain-induced sensitization of secondary neurons in spinal cord. Therefore, cortistatin emerges as an anti-inflammatory factor with potent analgesic effects that offers a new approach to clinical pain therapy, especially in inflammatory states