Deletion of the inducible nitric oxide synthase gene reduces peripheral morphine tolerance in a mouse model of chronic inflammation.
The implication of inducible nitric-oxide synthase (iNOS) on peripheral tolerance to morphine was evaluated in wild-type (WT) and iNOS knockout mice. Chronic inflammation was induced by subplantar (s.p.) injection of Complete Freund's Adjuvant (CFA), and morphine tolerance by subcutaneous implantation of a 75 mg morphine-pellet. Withdrawal was assessed after the intraperitoneal injection of 2 mg/kg naloxone. Antinociception was assessed (Randall-Selitto test) 5 min after a fixed dose of s.p. morphine (16 microg). In the absence of inflammation, s.p. morphine did not induce antinociception, while during CFA-inflammation produced 47.4 +/- 0.8 and 38.8 +/- 2.7% inhibitions respectively, in each genotype (P < 0.05). In morphine-tolerant mice with CFA-inflammation, no antinociception could be elicited in WT mice (2.4 +/- 0.3% inhibition); however, iNOS knockout mice showed significant antinociception (33.1 +/- 0.9%) (P < 0.001). Thus, iNOS gene deletion partially prevented tolerance to the peripheral effects of morphine, and significantly attenuated withdrawal-induced hyperactivity.
Romero
Asunción
A
Department of Anaesthesiology, Pain Research Unit, IMIM-Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.
Hernández
Laura
L
García-Nogales
Paula
P
Puig
Margarita M
MM
D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002908:Chronic Disease; D004195:Disease Models, Animal; D004361:Drug Tolerance / Q000502:physiology*; D017353:Gene Deletion; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics; D018836:Inflammation Mediators / Q000008:administration & dosage / Q000009:adverse effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000008:administration & dosage* / Q000009:adverse effects; D009270:Naloxone / Q000008:administration & dosage; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D013375:Substance Withdrawal Syndrome / Q000201:enzymology / Q000235:genetics / Q000473:pathology
D018836:Inflammation Mediators; D009270:Naloxone; D009020:Morphine; D052247:Nitric Oxide Synthase Type II