Conditional mu-cKO mice show decreased opiate-induced analgesia in the CFA-induced inflammatory pain model.

<p>(<b>A</b>) Two days after CFA, morphine (i.p.) dose-dependently reduced heat and mechanical hypersensitivities in mu^fl control mice. This analgesia was diminished in mu-cKO mice. Dashed lines represent baseline (pre-CFA) sensitivities. White bars, mu^fl mice; black bars, mu-cKO mice. For plantar test, n=13-20/genotype. two-way ANOVA (genotype x treatment F(1,90) = 75.336, <i>P</i> <0.001 for treatment; F(1,90) = 23.313, <i>P</i> <0.001 for genotype. Post-hoc Bonferroni test, ✰✰✰ <i>P</i><0.001, morphine <i>vs</i> saline; ★★ <i>P</i><0.01, ★★★ <i>P</i><0.001 cKO vs flox controls. For Von Frey filaments test, n=7-18/genotype. two-way ANOVA (genotype x treatment F(1,91) = 41.573, <i>P</i> <0.001 for treatment; F(1,91) = 27.378, <i>P</i> <0.001 for genotype. Post-hoc Bonferroni test, ✰✰ <i>P</i><0.01, ✰✰✰ <i>P</i><0.001 morphine <i>vs</i> saline; ★ <i>P</i><0.05, ★★ <i>P</i><0.01 mu-cKO vs mu^fl controls. (<b>B</b>) Fentanyl produced a dose-dependent analgesia in mu^fl control mice 2 days after CFA. Mu-cKO mice displayed a decreased analgesic response in the mechanical sensitivity test for the 0.03 mg/kg fentanyl dose. n=5-10/genotype. For plantar test, two-way ANOVA (genotype X treatment F(1,54) = 8.979, <i>P</i> <0.001 for treatment, <i>P</i>= 0.19 for genotype), post-hoc Bonferroni test; ✰✰ <i>P</i> <0.01, ✰✰✰ <i>P</i><0.001, fentanyl 0.1 mg/kg <i>vs</i> saline; for fentanyl 0.03 mg/kg, <i>P</i> = 0.0675 in mu^fl animals, <i>P</i> = 0.21 in mu-cKO animals. For Von Frey test, two-way ANOVA (genotype X treatment F(1,45) = 22.802, <i>P</i> <0.001 for treatment, F(1,45) = 9.316, <i>P</i> <0.01 for genotype). Post-hoc Bonferroni test for treatment, ✰✰✰ <i>P</i><0.001, fentanyl 0.1 mg/kg <i>vs</i> saline; for fentanyl 0.03 mg/kg, <i>P</i> = 0.0575 mu^fl animals, <i>P</i> = 0.28 mu-cKO animals. Post-hoc Fisher test for genotype, ★ <i>P</i><0.05, mu-cKO vs mu^fl mice. (<b>C</b>) Morphine-induced analgesia is reduced by systemic administration of the peripheral antagonist naloxone methiodide (NM). Morphine (5 mg/kg) induced an antihyperalgesic effect in mu^fl mice for both heat and mechanical responses. Systemic NM diminished morphine-induced analgesia. Heat hypersensitivity, one-way ANOVA for treatment F(3,42) = 29.778, P<0.001 ; post-hoc Bonferroni test, ✰✰ <i>P</i> <0.01, ✰✰✰ <i>P</i> <0.001 morphine <i>vs</i> saline; ★★ <i>P</i><0.01 ★★★ <i>P</i><0.001 NM + morphine <i>vs</i> morphine. Mechanical hypersensitivity, one-way ANOVA for treatment F(3,52) = 23.467, P<0.001 ; post-hoc Bonferroni test, ✰✰✰ <i>P</i> <0.001 morphine <i>vs</i> saline; ★★★ <i>P</i><0.001 NM + morphine <i>vs</i> morphine.