title: Tolerance to the antinociceptive effects of peripherally administered opioids. Expression of beta-arrestins.
abstract: 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.
authors.affiliation: Anaesthesiology Research Unit, IMIM. Department of Anaesthesiology, Hospital del Mar, Universitat Autònoma de Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Hernández
authors.forename: Asunción
authors.initials: A
authors.lastname: Romero
authors.forename: Pilar
authors.initials: P
authors.lastname: Almela
authors.forename: Paula
authors.initials: P
authors.lastname: García-Nogales
authors.forename: M Luisa
authors.initials: ML
authors.lastname: Laorden
authors.forename: Margarita M
authors.initials: MM
authors.lastname: Puig
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005121:Extremities; D007249:Inflammation / Q000503:physiopathology; D008297:Male; D051379:Mice; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D011897:Random Allocation; D011957:Receptors, Opioid / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; D019390:Arrestins; D011957:Receptors, Opioid; D000071557:beta-Arrestins; D009020:Morphine