3.6 Neuropathic pain: Absence of MOPs in primary sensory neurons results in enhanced, bilateral, mechanical hypersensitivity after nerve injury
We investigated whether the absence of peripheral MOPs affects the development of SNIt-induced mechanical allodynia. Before nerve injury, PWFs of left and right hind paws were similar and did not differ significantly between genotypes. At 2 days after nerve injury, ipsilateral PWF in response to high force mechanical stimuli had increased significantly in WT mice from 38 ± 3.27% to 74 ± 5.62% and in Oprm1 cKO mice from 32 ± 4.16% to 66 ± 5.62% (Figure 7) . This nerve-injury induced increase in PWF was also observed in response to low force mechanical stimuli and persisted for up to 17 days post-injury. In the Oprm1 cKO group, withdrawal frequencies in the contralateral paw also increased significantly from pre-injury baseline values. This effect peaked 5 days post-injury, with PWF in response to high force mechanical stimuli increasing significantly from 29 ± 2.77% at baseline to 56 ± 3.06%. Notably, on day 5, allodynia to high force mechanical stimuli contralateral to nerve injury inOprm1 cKO mice was as severe as that in the ipsilateral paw of WT mice. The WT group did not exhibit an injury-induced increase in contralateral PWF to mechanical stimuli. Tests with Oprm1 cKO sham-operated mice confirmed that the peripheral MOP-mediated bilateral mechanical allodynia was induced by nerve injury (Supplemental Figure 2A ).
Deletion of MOPs in primary sensory neurons did not impair gross motor function after nerve injury. Post-SNIt rotarod activity did not differ between genotypes, and, when compared to their naïve counterparts, neither genotype showed significant differences in the open field test after nerve injury (Supplemental Figure 2B, C) . No significant differences were observed in the body weight of nerve-injured animals (not shown), and no sex-dependent differences were noted in their behavioral and motor activity (not shown).