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Brain Res. 2009 Jan 12;1248:31-9. doi: 10.1016/j.brainres.2008.10.065. Epub 2008 Nov 7.

Tolerance to the antinociceptive effects of peripherally administered opioids. Expression of beta-arrestins.

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  • 1Anaesthesiology Research Unit, IMIM. Department of Anaesthesiology, Hospital del Mar, Universitat Autònoma de Barcelona, Spain.


Tolerance to peripheral antinociception after chronic exposure to systemic morphine was assessed in mice with chronic CFA-inflammation; cross-tolerance to locally administered mu, delta and kappa-opioid agonists and levels of beta-arrestins in the injured paw, were also evaluated. Tolerance was induced by the subcutaneous implantation of a 75 mg morphine-pellet, and antinociception evaluated with the Randall-Selitto test, 5 min after the subplantar injection of morphine, fentanyl, buprenorphine, DPDPE, U-50488H or CRF. Experiments were performed in the absence and presence of CFA-inflammation, in animals implanted with a morphine or placebo pellet. Beta-arrestin protein levels were determined by western blot. In mice without inflammation, subplantar opioids did not induce antinociception, while during CFA-inflammation, all drugs generated dose-response curves with an order of potency of: U-50488H < DPDPE < morphine < buprenorphine < fentanyl << CRF. During CFA-inflammation plus morphine-pellet, the potency of fentanyl decreased 1.25 times, while that of DPDPE, U-50488H and CRF diminished approximately 2.5-4.3 times. For each drug, the ratio between the ED(50)'s in tolerant and naive animals, was significantly higher than 1 (except for buprenorphine and fentanyl), demonstrating partial cross-tolerance to systemic morphine. Inflammation induced a twofold increase in beta-arrestin expression (p<0.01), and the levels decreased after acute morphine exposure (p<0.05). Tolerance did not alter beta-arrestins, but partially prevented the increase induced by inflammation. The results suggest that peripheral beta-arrestins could facilitate peripheral OR-desensitization and tolerance development. Clinically, the experiments could be useful to establish the effectiveness of local opioid administration in patients with musculoskeletal pain, chronically receiving morphine analgesia.

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