3.5 Inflammatory pain: MOPs in primary sensory neurons are essential for the analgesic effect of DALDA and contribute to analgesia from morphine
We sought to determine whether MOPs in primary sensory neurons mediate the analgesic effects of opioids on acute and persistent inflammatory pain. In WT mice, s.c. injection of 5 mg∙kg-1 DALDA significantly reversed the CFA-induced inflammatory pain, as shown by an increase in PWL from 7.93 ± 0.69 s to 15.43 ± 1.01 s, 60 min after administration. Subcutaneous injection of the same DALDA dose produced no significant increase in PWL in the Oprm1 cKO group (Figure 6A) . In WT mice, we found that s.c. injection of 5 mg∙kg-1 morphine induced an antinociceptive effect, in addition to an antihyperalgesic response, as PWL increased from a CFA-induced low of 6.68 ± 0.35 s to 18.34 ± 0.43 s 30 min after administration, compared to a pre-injury baseline PWL of 13.92 ± 0.73 s(Figure 6B) . Morphine’s analgesic effect in WT mice peaked at 30 min and lasted for approximately 90 min. In contrast, the same dose of morphine in Oprm1 cKO mice had a significantly smaller effect, increasing PWL from 5.81 ± 0.43 s to 9.33 ± 0.66 s 30 min after administration, relative to a pre-injury baseline of 14.26 ± 0.74 s. As in WT mice, the response to morphine peaked 30 min after drug administration. In the Oprm1 cKO group, the overall effect of morphine lasted for approximately 60 min, and unlike in the WT cohort, did not fully reverse the CFA-induced reduction in PWL.
Additional studies confirmed that absence of MOPs in primary sensory neurons does not affect the development and severity of CFA-induced inflammation and thermal hyperalgesia. Response to thermal stimuli(Figure 6C) and paw edema measurements (Figure 6D)were evaluated before and at 24 and 72 hr after CFA injection. No significant differences were observed between genotypes. Contralateral paw data showed that the effects of CFA were unilateral in both WT andOprm1 cKO mice. No sex differences were observed in the drug- and CFA-induced effects. These results verify that the drug effects were tested under comparable pain sensitivities in the two genotypes.