title: When is the maximal effect of pre-administered systemic morphine on carrageenin evoked spinal c-Fos expression in the rat?
abstract: This study evaluated, in awake rats, the time course of the expression of c-Fos in spinal cord neurons, in the L4-L5 segments, at various time points after intraplantar carrageenin (0.5 h, 1 h, 1.5 h, 2 h and 2.5 h). In addition, the effects of pre-administered morphine (3 mg/kg, i.v.) on the c-Fos expression, at the various time points, were studied. Very few Fos-like immunoreactive (Fos-LI) neurons were observed 0.5 h after carrageenin. However, spinal c-Fos expression increased initially (at 1 h), in the superficial laminae (I-II) of the spinal dorsal horn, and incrementally increased both in the superficial and deep (V-VI) laminae at later time points after carrageenin. Systemic morphine did not significantly decrease the number of superficial Fos-LI neurons observed 1 h after carrageenin, whereas it significantly reduced the number of superficial Fos-LI neurons induced at 1.5 h and 2 h after carrageenin (58 +/- 3% and 57 +/- 10% reduction, P < 0.001, respectively). In addition, morphine reduced the number of deep Fos-LI neurons at 1.5 h and 2 h after carrageenin (86 +/- 4%, P < 0.01 and 82 +/- 8%, P < 0.001 reduction as compared to control carrageenin expression, respectively). In contrast, morphine was less efficacious in decreasing the number of Fos-LI neurons observed in the superficial and deep laminae at 2.5 h after carrageenin (34 +/- 6% and 59 +/- 6% reduction, P < 0.001, respectively). Thus, the peak effect of pre-administered morphine on carrageenin evoked c-Fos expression was observed 1.5 h and 2 h after intraplantar carrageenin, with a weaker effect observed at 2.5 h after carrageenin. The pharmacokinetic complications between the time course of the antinociceptive effects of morphine and c-Fos expression is discussed. These results clearly demonstrate that studies of c-Fos expression with pharmacological investigations should take into consideration this finding since one delay after the stimulation does not give a full indication of the full potential of the drug tested.
authors.affiliation: Physiopharmacologie du Système Nerveux, INSERM U.161, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Honoré
authors.forename: V
authors.initials: V
authors.lastname: Chapman
authors.forename: J
authors.initials: J
authors.lastname: Buritova
authors.forename: J M
authors.initials: JM
authors.lastname: Besson
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan / Q000494:pharmacology; D007150:Immunohistochemistry; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009187:Myelitis / Q000139:chemically induced; D009474:Neurons / Q000737:chemistry / Q000187:drug effects; D009619:Nociceptors / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis / Q000096:biosynthesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology* / Q000378:metabolism; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D016760:Proto-Oncogene Proteins c-fos; D009020:Morphine; D002351:Carrageenan