Tolerance to the antinociceptive effects of peripherally administered opioids: Expression of β-arrestins

Tolerance to peripheral antinociception after chronic exposure to systemic morphine was assessed in mice with chronic CFA-inflammation; cross-tolerance to locally administered μ, δ and κ-opioid agonists and levels of β-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 ED50'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 β-arrestin expression (p < 0.01), and the levels decreased after acute morphine exposure (p < 0.05). Tolerance did not alter β-arrestins, but partially prevented the increase induced by inflammation. The results suggest that peripheral β-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.