title: Role of peripheral versus spinal 5-HT(7)  receptors in the modulation of pain undersensitizing conditions.
abstract: Several studies have suggested that 5-HT(7)  receptors are involved in nociceptive processing but the exact contribution of peripheral versus central 5-HT(7)  receptors still needs to be elucidated. In the present study, the respective roles of peripheral and spinal 5-HT(7)  receptors in the modulation of mechanical hypersensitivity were investigated under two different experimental pain conditions. In a first set of experiments, the selective 5-HT(7)  receptor agonist, E-57431, was systemically, intrathecally or peripherally (intraplantarly) administered to rats sensitized by intraplantar injection of capsaicin. Oral administration of E-57431 (1.25-10 mg/kg) was found to exert a clear-cut dose-dependent reduction of capsaicin-induced mechanical hypersensitivity. Interestingly, intrathecal administration of E-57431 (100 μg) also inhibited mechanical hypersensitivity secondary to capsaicin injection. In contrast, a dose-dependent enhancement of capsaicin-induced mechanical hypersensitivity was observed after local intraplantar injection of E-57431 (0.01-1 μg). In a second set of experiments, E-57431 was systemically or intrathecally administered to rats submitted to neuropathic pain (spared nerve injury model). Significant inhibition of nerve injury-induced mechanical hypersensitivity was found after intraperitoneal (10 mg/kg) as well as intrathecal (100 μg) administration of E-57431 in this chronic pain model. These studies provide evidence that, under sensitizing neurogenic/neuropathic conditions, activation of 5-HT(7)  receptors exerts antinociceptive effects at the level of the spinal cord and pronociceptive effects at the periphery. The antinociceptive effect mediated by central 5-HT(7)  receptors seems to predominate over the pronociceptive effect at the periphery when a selective 5-HT(7)  receptor agonist is systemically administered.
authors.affiliation: Department of Pharmacology, Drug Discovery and Preclinical Development, ESTEVE. Av. Mare de Déu de Montserrat, 221, 08041, Barcelona, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Brenchat
authors.forename: D
authors.initials: D
authors.lastname: Zamanillo
authors.forename: M
authors.initials: M
authors.lastname: Hamon
authors.forename: L
authors.initials: L
authors.lastname: Romero
authors.forename: J M
authors.initials: JM
authors.lastname: Vela
mesh_terms: D015078:2-Hydroxyphenethylamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin; D003714:Denervation; D004305:Dose-Response Relationship, Drug; D005528:Foot; D007267:Injections; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D010525:Peripheral Nerves / Q000503:physiopathology*; D010812:Physical Stimulation; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D020426:Sciatic Neuropathy / Q000503:physiopathology; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D013116:Spinal Cord / Q000503:physiopathology*
chemical_list: C572492:2-(2-(dimethylamino)ethyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)phenol; D011720:Pyrazoles; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C104425:serotonin 7 receptor; D015078:2-Hydroxyphenethylamine; D002211:Capsaicin