Chronic treatment with systemic morphine induced tolerance to the systemic and peripheral antinociceptive effects of morphine on both carrageenin induced mechanical hyperalgesia and spinal c-Fos expression in awake rats.
The effects of intravenous (3 mg/kg i.v.) and intraplantar (50 micrograms/50 microliters i.pl.) morphine were investigated on spinal c-Fos expression induced 2 h after intraplantar carrageenin (6 mg/150 microliters of saline) and on carrageenin (2 mg/150 microliters of saline) induced mechanical hyperalgesia, at day 4, in both naive and chronic morphine treated (80 mg/kg/day s.c. on days 1, 2 and 3) rats. In naive rats, i.v. and i.pl. morphine significantly decreased spinal c-Fos expression (64 +/- 4% and 44 +/- 4% reduction of control carrageenin c-Fos expression, P < 0.0001 for both, respectively) and mechanical hyperalgesia (maximal increase: 326 +/- 29%, P < 0.0001 and 87 +/- 5%, P < 0.005 of control carrageenin paw pressure vocalisation threshold (VTPP), respectively), which only developed in the carrageenin injected paw. Both treatments were ineffective in chronic morphine treated rats (92 +/- 9% and 106 +/- 6% of control carrageenin c-Fos expression; 33 +/- 17% and 30 +/- 15% increase of control carrageenin VTPP, respectively). Furthermore, only i.v. morphine increased the VTPP in the contralateral paw, in naive rats (maximal increase: 90 +/- 8%, P < 0.0001 of control carrageenin VTPP), its effects being significantly less pronounced than for the inflamed paw (P < 0.0001). These studies based on spinal c-Fos expression as an indirect marker of spinal nociceptive processes and on behavioural experiments clearly revealed that chronic treatment with systemic morphine induced tolerance to both its systemic and peripheral effects.
Honoré
P
P
Physiopharmacologie du Système Nerveux, INSERM U161, Paris, France. honore@broca.inserm.fr
Catheline
G
G
Le Guen
S
S
Besson
J M
JM
D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002351:Carrageenan; D004361:Drug Tolerance; D004487:Edema / Q000139:chemically induced / Q000473:pathology; D005528:Foot; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D007150:Immunohistochemistry; D007267:Injections; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D010812:Physical Stimulation; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology
D000701:Analgesics, Opioid; D016760:Proto-Oncogene Proteins c-fos; D009020:Morphine; D002351:Carrageenan