title: Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia.
abstract: We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.
authors.affiliation: Centre de Recherche Pierre Fabre, 17, Avenue Jean Moulin, 81106 Castres Cedex, France. francis.colpaert@pierre-fabre.com
authors.forename: F C
authors.initials: FC
authors.lastname: Colpaert
authors.forename: J P
authors.initials: JP
authors.lastname: Tarayre
authors.forename: W
authors.initials: W
authors.lastname: Koek
authors.forename: P J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: L
authors.initials: L
authors.lastname: Bardin
authors.forename: X-J
authors.initials: XJ
authors.lastname: Xu
authors.forename: Z
authors.initials: Z
authors.lastname: Wiesenfeld-Hallin
authors.forename: C
authors.initials: C
authors.lastname: Cosi
authors.forename: E
authors.initials: E
authors.lastname: Carilla-Durand
authors.forename: M B
authors.initials: MB
authors.lastname: Assié
authors.forename: B
authors.initials: B
authors.lastname: Vacher
mesh_terms: D000085:Acetates / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000588:Amines; D000631:Aminopyridines / Q000819:agonists / Q000494:pharmacology*; D000698:Analgesia; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003509:Cyclohexanecarboxylic Acids; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes / Q000662:veterinary; D004334:Drug Administration Schedule / Q000662:veterinary; D004357:Drug Synergism; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage; D000077206:Gabapentin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006930:Hyperalgesia / Q000139:chemically induced; D007099:Imipramine / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection; D005680:gamma-Aminobutyric Acid
chemical_list: D000085:Acetates; D018759:Adrenergic Uptake Inhibitors; D000588:Amines; D000631:Aminopyridines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D018490:Serotonin Agents; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005680:gamma-Aminobutyric Acid; D007649:Ketamine; D000077206:Gabapentin; D009020:Morphine; D007099:Imipramine; C473959:befiradol; D005283:Fentanyl