1. Large-amplitude 5-HT1A receptor activation: a new mechanism of profound, central analgesia
- Author
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Francis Colpaert, Wouter Koek, M.B. Assié, Elisabeth Carilla-Durand, Bernard Vacher, Xiao Jun Xu, Cristina Cosi, Petrus J. Pauwels, L. Bardin, J.P. Tarayre, and Zsuzsanna Wiesenfeld-Hallin
- Subjects
Male ,Imipramine ,Time Factors ,Cyclohexanecarboxylic Acids ,Pyridines ,Aminopyridines ,Pharmacology ,Acetates ,Befiradol ,Rats, Sprague-Dawley ,Radioligand Assay ,Serotonin Agents ,Piperidines ,Cricetinae ,Medicine ,Amines ,Cells, Cultured ,gamma-Aminobutyric Acid ,Pain Measurement ,Analgesics ,Adrenergic Uptake Inhibitors ,Morphine ,Drug Administration Routes ,Drug Synergism ,Fentanyl ,Allodynia ,Nociception ,Hyperalgesia ,Anesthesia ,Neuropathic pain ,Female ,Ketamine ,medicine.symptom ,Gabapentin ,medicine.drug ,Pain Threshold ,Analgesic ,Pain ,CHO Cells ,Transfection ,Drug Administration Schedule ,Cellular and Molecular Neuroscience ,Animals ,Dose-Response Relationship, Drug ,business.industry ,Rats ,Disease Models, Animal ,Guanosine 5'-O-(3-Thiotriphosphate) ,Receptors, Serotonin ,Analgesia ,business ,Receptors, Serotonin, 5-HT1 - 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.
- Published
- 2002