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Deletion of the inducible nitric oxide synthase gene reduces peripheral morphine tolerance in a mouse model of chronic inflammation
Author(s) -
Romero Asunción,
Hernández Laura,
GarcíaNogales Paula,
Puig Margarita M.
Publication year - 2010
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.2009.00775.x
Subject(s) - morphine , nitric oxide synthase , inflammation , pharmacology , nitric oxide , (+) naloxone , knockout mouse , peripheral , subcutaneous injection , intraperitoneal injection , drug tolerance , chemistry , endocrinology , medicine , opioid , receptor
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 μg). 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.