Clinical
pain, as a consequence of
inflammation or injury of peripheral organs (inflammatory
pain) or nerve injury (
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 nociceptive neurons of the dorsal root ganglia in response to inflammatory and noxious stimuli. Moreover,
cortistatin is produced by GABAergic interneurons of deep layers of dorsal horn of spinal cord. By using
cortistatin-deficient mice, we demonstrated that endogenous
cortistatin critically tunes pain perception in physiological and pathological 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 exerted on peripheral and central nociceptive terminals via Gαi-coupled
somatostatin-receptors (mainly sstr2) and blocking intracellular signaling that drives neuronal plasticity including
protein kinase A-,
calcium- and Akt/ERK-mediated release of nociceptive
peptides. Moreover,
cortistatin could modulate, through its binding 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.