title: 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 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.
authors: Institute of Parasitology and Biomedicine Lopez-Neyra, IPBLN-CSIC, 18016 Granada, Spain.
authors: María
authors: M
authors: Morell
authors: Institute of Molecular and Cell Biology, Miguel Hernandez University, 03202 Alicante, Spain.
authors: María
authors: M
authors: Camprubí-Robles
authors: IPSEN Group, Milford, MA 01757, USA.
authors: Michael D
authors: MD
authors: Culler
authors: Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
authors: Luis
authors: L
authors: de Lecea
authors: Institute of Parasitology and Biomedicine Lopez-Neyra, IPBLN-CSIC, 18016 Granada, Spain. Electronic address: mdelgado@ipb.csic.es.
authors: Mario
authors: M
authors: Delgado
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004333:Drug Administration Routes; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology; D007249:Inflammation / Q000150:complications / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects; D009479:Neuropeptides / Q000172:deficiency / Q000378:metabolism*; D009578:Nitrobenzenes / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D013449:Sulfonamides / Q000627:therapeutic use; D013997:Time Factors
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009479:Neuropeptides; D009578:Nitrobenzenes; D013449:Sulfonamides; C099323:cortistatin; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
keywords: Allodynia; Dorsal root ganglia; Inflammatory pain; Neuropeptide; Nociceptor; Spinal cord