title: Systemic cannabinoids produce CB₁-mediated antinociception by activation of descending serotonergic pathways that act upon spinal 5-HT(7) and 5-HT(2A) receptors.
abstract: Serotonin (5-HT) plays an important role in the descending control of pain. We evaluated the role of descending serotonergic pathways and spinal 5-HT₇ and 5-HT(2A) receptors in comparison to that of 5-HT(1A) and 5-HT₃ receptors in the antinociceptive effects of systemically administered cannabinoids. Antinociceptive effects were evaluated by radiant heat tail-flick and hot plate tests in Balb-C mice. The selective CB₁ receptor agonist, ACEA; a mixed CB₁ and CB₂ receptor agonist, WIN 55,212-2; and a selective CB₂ receptor agonist, GW405833, were given systemically to induce antinociception. Spinal 5-HT was depleted with intrathecal (i.th.) injection of 5,7-dihydroxytryptamine (5,7-DHT). Bilateral surgical lesions of the dorsolateral funiculus were performed. Selective 5-HT₇, 5-HT(2A), 5-HT(1A) and 5-HT₃ antagonists-SB-269970, ketanserin, WAY 100635 and ondansetron, respectively-were administered i.th. Risperidone, an atypical antipsychotic displaying 5-HT(2A) antagonism, also irreversibly binds to and inactivates the 5-HT₇ receptors. Thus, we also injected risperidone i.th. to elucidate the role of spinal 5-HT₇ and 5-HT(2A) receptors in cannabinoid-mediated antinociception. WIN 55,212-2 and ACEA produced dose-dependent antinociception, which were reversed by selective CB₁ receptor antagonist rimonabant. GW405833 did not produce any antinociception. The antinociceptive effects of WIN 55,212-2 and ACEA were totally absent in spinal 5-HT depleted and dorsolateral funiculus lesioned mice. I.th. administration of SB-269970, ketanserin, and risperidone, but not WAY 100635 or ondansetron, blocked both WIN 55,212-2- and ACEA-induced antinociception. These findings suggest that systemically administered cannabinoids interact with descending serotonergic pathways via CB₁-mediated mechanisms and exert a central antinociceptive effect involving spinal 5-HT₇ and 5-HT(2A) receptors.
authors.affiliation: Department of Medical Pharmacology, Gulhane Military Academy of Medicine, 06018 Ankara, Turkey.
authors.forename: Melik
authors.initials: M
authors.lastname: Seyrek
authors.forename: Serdar
authors.initials: S
authors.lastname: Kahraman
authors.forename: Mehmet Salih
authors.initials: MS
authors.lastname: Deveci
authors.forename: Ozgur
authors.initials: O
authors.lastname: Yesilyurt
authors.forename: Ahmet
authors.initials: A
authors.lastname: Dogrul
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D002186:Cannabinoids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006358:Hot Temperature / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010147:Pain Measurement; D020033:Protein Isoforms / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D011985:Receptors, Serotonin / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; D002186:Cannabinoids; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; D018490:Serotonin Agents; D012702:Serotonin Antagonists; C104425:serotonin 7 receptor