Left-right side-specific neuropeptide mechanism mediates contralateral responses to a unilateral brain injury

Neuropeptides are implicated in control of lateralized processes in the brain. A unilateral brain injury (UBI) causes the contralesional sensorimotor deficits. To examine whether opioid neuropeptides mediate UBI induced asymmetric processes we compared effects of opioid antagonists on the contralesional and ipsile-sional hindlimb responses to the left-sided and right-sided injury in rats. UBI induced hindlimb postural asymmetry (HL-PA) with the contralesional hindlimb flexion, and activated contralesional withdrawal reflex of extensor digitorum longus (EDL) evoked by electrical stimulation and recorded with EMG technique. No effects on the interossei (Int) and peroneaus longus (PL) were evident. The general opioid antagonist naloxone blocked postural effects, did not change EDL asymmetry while uncovered cryptic asymmetry in the PL and Int reflexes induced by UBI. Thus, the spinal opioid system may either mediate or counteract the injury effects. Strikingly, effects of selective opioid antagonists were the injury side-specific. The *-antagonist ß-funaltrex-amine (FNA) and ¿-antagonist nor-binaltorphimine (BNI) reduced postural asymmetry after the right but not left UBI. In contrast, the d-antagonist naltrindole (NTI) inhibited HL-PA after the left but not right-side brain injury. The opioid gene expression and opioid peptides were lateralized in the lumbar spinal cord, and coordination between expression of the opioid and neuroplasticity-related genes was impaired by UBI that together may underlie the side-specific effects of the antagonists. We suggest that mirror-symmetric neural circuits that mediate effects of left and right brain injury on the contralesional hindlimbs are differentially controlled by the lateralized opioid system. ; The work was supported by Swedish Research Council Grants K2014-62X-12190-19-5 and 2019-01771-3 (to G.B.) and 2016-06195 (to J.S.), L. Hiertas Minne Foundation and P.O. Zetterling Foundation (to O.N.), Uppsala University (to G.B.), Lund University and Skåne County Council Grant ...