title: Evidence for the participation of cocaine- and amphetamine-regulated transcript peptide (CART) in the fluoxetine-induced anti-hyperalgesia in neuropathic rats.
abstract: Cocaine- and amphetamine-regulated transcript peptide (CART) has a role in chronic pain, and also in the 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, fluoxetine, in neuropathic rats. Sciatic nerve in the right hind paw of rat was ligated to induce neuropathic pain, and the paw withdrawal latency was evaluated using Hargreaves apparatus. Fluoxetine [5-25mg/kg, intraperitoneal (ip)] or CART (54-102) [0.1-1.5μg/rat, intracerebroventricular (icv)] dose-dependently attenuated the hyperalgesic response observed in neuropathic rats, indicating anti-nociceptive properties 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; 5μl/rat, icv); CART-antibody had no effect per se. Isobolographic analysis showed a significant synergism between fluoxetine and CART, and antagonism between fluoxetine and CART-antibody. Immunocytochemical labeling with monoclonal antibodies against CART showed drastic increase in CART-immunoreactive fibers in the ventrolateral periaqueductal gray (VLPAG; 116%), dorsal subdivision of dorsal raphe nucleus (DRD; 176%), and locus coeruleus (LC; 733%) of neuropathic animals. Fluoxetine treatment significantly reduced the immunoreactivity in these areas. However, CART-immunoreactive cells and fibers in the arcuate nucleus did not respond to neuropathy 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.
authors.affiliation: Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Nagpur 440033, India.
authors.forename: Manoj A
authors.initials: MA
authors.lastname: Upadhya
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Dandekar
authors.forename: Dadasaheb M
authors.initials: DM
authors.lastname: Kokare
authors.forename: Praful S
authors.initials: PS
authors.lastname: Singru
authors.forename: Nishikant K
authors.initials: NK
authors.lastname: Subhedar
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005473:Fluoxetine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy* / Q000378:metabolism; D057967:Infusions, Intraventricular; D008026:Ligation; D008125:Locus Coeruleus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D010147:Pain Measurement; D010487:Periaqueductal Gray / Q000187:drug effects / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000601:surgery; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein
chemical_list: D000906:Antibodies; D009419:Nerve Tissue Proteins; D000098882:Cocaine- and Amphetamine-Regulated Transcript Protein; D005473:Fluoxetine