Evidence for the participation of cocaine- and amphetamine-regulated transcript peptide (CART) in the fluoxetine-induced anti-hyperalgesia in neuropathic rats

Abstract

Cocaine-andamphetamine-regulatedtranscriptpeptide(CART)hasaroleinchronicpain,andalsointhe actions of selective serotonin reuptake inhibitors (SSRIs) employed in the treatment of neuropathic pain. Herein, we test the hypothesis that CART may mediate the anti-hyperalgesic effect of the SSRI, fluoxe tine, in neuropathic rats. Sciatic nerve in the right hindpawofratwasligatedtoinduceneuropathicpain, and the paw withdrawal latency was evaluated using Hargreaves apparatus. Fluoxetine [5–25mg/kg, intraperitoneal (ip)] or CART (54–102) [0.1–1.5 g/rat, intracerebroventricular (icv)] dose-dependently attenuated the hyperalgesic response observed in neuropathic rats, indicating anti-nociceptive proper ties of each agent. The anti-hyperalgesic effect of fluoxetine was potentiated by the subeffective dose of CART, and attenuated by CART-antibody (1:500 dilution; 5 l/rat, icv); CART-antibody had no effect per se. Isobolographic analysis showed a significant synergism between fluoxetine and CART, and antago nismbetweenfluoxetineandCART-antibody.Immunocytochemicallabelingwithmonoclonalantibodies againstCARTshoweddrasticincreaseinCART-immunoreactivefibersintheventrolateralperiaqueductal gray (VLPAG; 116%), dorsal subdivision of dorsal raphe nucleus (DRD; 176%), and locus coeruleus (LC; 733%)ofneuropathic animals. Fluoxetine treatment significantly reduced the immunoreactivity in these areas. However, CART-immunoreactive cells and fibers in the arcuate nucleus did not respond to neu ropathy or fluoxetine treatments. We suggest that the CART innervation of DRD, LC and VLPAG may be involved in the (i) central processing of neuropathic pain and (ii) fluoxetine-induced anti-hyperalgesic effect in neuropathic pain.