The novel analgesic and high-efficacy 5-HT1A receptor agonist, F 13640 induces c-Fos protein expression in spinal cord dorsal horn neurons.
The very-high-efficacy, selective 5-HT(1A) receptor agonist, F 13640 produces uniquely powerful analgesia in rat models of chronic pain by novel neuroadaptive mechanisms (inverse tolerance and co-operation with nociception) [Neuropharmacology 43 (2002) 945-958]. A signal transduction theory and evidence suggest that F 13640 initiates these mechanisms, paradoxically, by mimicking the central effects of nociceptive stimulation. We report that the i.p. injection of F 13640 induces c-Fos protein expression in the L3-L5 segments of the spinal cord. Some 65% of c-Fos protein immunoreactive (c-Fos-IR) nuclei occurred bilaterally in the dorsal horn laminae I-II and V-VI, spinal areas that contain neurons responsive to nociceptive stimulation. This pattern is not unlike that found earlier in arthritic rats, a model of somatotopically widespread nociception. Dose-response studies indicated that c-Fos protein expression was induced at doses (0.63 and 2.5 mg/kg, i.p.) at which previous studies had found F 13640 to produce hyperalgesia. Time-response studies found that c-Fos-IR nuclei appeared within 1-4 h after 0.63 mg/kg of F 13640, with a maximum at 2 h. This parallels literature evidence that c-Fos expression reaches peak late after, and outlasts, nociceptive stimulation. Similar to opioids counteracting noxiously induced c-Fos expression, 10 mg/kg (s.c.) of morphine reduced the number of c-Fos-IR nuclei induced by 0.63 mg/kg of F 13640 (by 45+/-5%; P<0.001). The induction by F 13640 of c-Fos protein expression may relate to the initial hyperalgesia which earlier data indicate the agent to produce early upon its administration.
Centre de Recherche Pierre Fabre, 17 avenue Jean Moulin, 81106 Castres Cedex 06, France. jaroslava.buritova@pierre-fabre.com
Jaroslava
J
Buritova
Jean-Pierre
JP
Tarayre
Jean-Marie
JM
Besson
Francis
F
Colpaert
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D016762:Genes, fos / Q000187:drug effects*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008297:Male; D009020:Morphine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects*; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D009020:Morphine; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C473959:befiradol; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide