Abstract
There are only a few studies on the molecular mechanisms underlying the peripheral antihyperalgesic effect of opioids. The aim of this study was to investigate the molecular bases of the peripheral antihyperalgesic effect of fentanyl in a model of prostaglandin-induced chemical hyperalgesia. Prostaglandin E2 (1.4 nmol) injected into one hind paw of male Wistar rats (200-250 g, N = 6 in each experimental or control group) pretreated with indomethacin (2.5 mg/kg) potentiated the nocifensive response to formalin (1%) injection made 60 min later. Drugs applied locally 30 min after prostaglandin E2 induced the following effects: fentanyl (0.1-1.0 nmol) caused a dose-dependent reversal of the hyperalgesic state, naloxone (2 nmol) co-injected with fentanyl (1 nmol) completely reversed the antihyperalgesic effect, Nomega-nitro-L-arginine (NOARG, 0.05-0.2 mol) in combination with fentanyl (1.0 nmol) caused a dose-dependent inhibition of the antihyperalgesic effect of fentanyl, co-administration of L-arginine (0.5 mol) with NOARG (0.2 mol) plus fentanyl (1.0 nmol) fully restored the antihyperalgesic effect, and the cyclic-GMP phosphodiesterase inhibitor UK-114,542-27 (5-[2-ethoxy-5-(morpholinylacetyl) phenyl]-1,6-dihydro-1-methyl-3-propyl-7H-pyrazolo [4,3-d]-pyrimidin-7-one methanesulfonate monohydrate; 0.5-2.0 mol) potentiated a subeffective dose of fentanyl (0.1 nmol) in a dose-dependent manner. However, UK-114,542-27 (2.0 mol) injected alone did not produce this antihyperalgesic effect. Systemically administered fentanyl (1.0 nmol, sc) did not cause antinociception. Taken together, these results support the view that fentanyl reverses prostaglandin E2-induced hyperalgesia, probably by activating an opioid receptor at the periphery, and furthermore the L-arginine/nitric oxide/cyclic-GMP pathway may mediate this peripheral effect of fentanyl.
Highlights
Sensitization of nociceptors is common to all types of inflammatory pain
Administered fentanyl (1.0 nmol, sc) did not cause antinociception. These results support the view that fentanyl reverses prostaglandin E2-induced hyperalgesia, probably by activating an opioid receptor at the periphery, and the L-arginine/nitric oxide/cyclic-GMP pathway may mediate this peripheral effect of fentanyl
The participation of the nitric oxide/cGMP pathway in the peripheral antinociceptive effect of other types of opiate-like drugs has not been firmly established. In view of these considerations, we evaluated the peripheral effect of the meperidine derivative fentanyl, which is structurally different from morphine, in a model of prostaglandin E2- (PGE2) induced hyperalgesia followed by chemical stimulation with formalin
Summary
Sensitization of nociceptors is common to all types of inflammatory pain. Analgesic drugs that act upon inflammatory sites may either prevent sensitization of the nociceptors or directly antagonize the ongoing hyperalgesia [1]. Acetylcholine and sodium nitroprusside [2], diclofenac [3], dipyrone [4], ketorolac [5] and opioid agonists [6,7] have a direct peripheral inhibitory effect on the hyperalgesia induced by inflammation or inflammatory mediators. Among these drugs, the peripheral antihyperalgesic effect of opioids has been most intensely investigated, and has been shown to be mediated by μ, δ or κ receptor subtypes, apparently depending on the sensitization protocol [8,9,10,11,12]. Morphine-nitric oxide coupling has been studied in prostaglandininduced mechanical hyperalgesia, but has yet to be systematically investigated with other types of stimuli
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