Ipsilesional versus contralesional postural deficits induced by unilateral brain trauma: a side reversal by opioid mechanism

Abstract

Unilateral traumatic brain injury and stroke result in asymmetric postural and motor deficits including contralateral hemiplegia and hemiparesis. In animals, a localized unilateral brain injury recapitulates the human upper motor neuron syndrome in formation of hindlimb postural asymmetry with contralesional limb flexion and the asymmetry of hindlimb nociceptive withdrawal reflexes. The current view is that these effects are developed due to aberrant activity of motor pathways that descend from the brain into the spinal cord. These pathways and their target spinal circuits may be regulated by local neurohormonal systems that may also mediate effects of brain injury. Here we evaluate if a unilateral traumatic brain injury induces hindlimb postural asymmetry, a model of postural deficits, and if this asymmetry is spinally encoded and mediated by the endogenous opioid system in rats. A unilateral right-sided controlled cortical impact, a model of clinical focal traumatic brain injury was centered over the sensorimotor cortex and was observed to induce hindlimb postural asymmetry with contralateral limb flexion. The asymmetry persisted after complete spinal cord transection, implicating local neurocircuitry in the development of the deficits. Administration of the general opioid antagonist naloxone and µ-antagonist β-funaltrexamine blocked formation of postural asymmetry. Surprisingly, κ-antagonists nor-binaltorphimine and LY2444296 did not affect the asymmetry magnitude but reversed the flexion side; instead of contralesional (left) hindlimb flexion the ipsilesional (right) limb was flexed. The postural effects of the right-side cortical injury were mimicked in animals with intact brain via intrathecal administration of the opioid κ-agonist U50,488 that induced hindlimb postural asymmetry with left limb flexion. The δ-antagonist naltrindole produced no effect on the contralesional (left) flexion but inhibited formation of the ipsilesional (right) limb flexion in brain-injured rats that were treated with κ-antagonist. The effects of the antagonists were evident before and after spinal cord transection. We concluded that the focal traumatic brain injury-induced postural asymmetry was encoded at the spinal level, and was blocked or its side was reversed by administration of opioid antagonists. The findings suggest that the balance in activity of the mirror symmetric spinal neural circuits regulating contraction of the left and right hindlimb muscles is controlled by receptors; and that this equilibrium is impaired after unilateral brain trauma through side-specific opioid mechanism.

Left-Right Side-Specific Neuropeptide Mechanism Mediates Contralateral Responses to a Unilateral Brain Injury

“…These findings corroborate the recent observations that selective opioid antagonists modulate the effects of the controlled cortical impact, a model of clinical focal TBI (Watanabe et al, 2020) Similar to the present study, administration of naloxone and β-funaltrexamine but not NTI blocked HL-PA induced by the unilateral right-sided TBI. However, the -antagonists nor-BNI and LY2444296 did not affect the magnitude of the asymmetry after the right side TBI, while the side there flexion occurred was reversed.…”

“…7C) (Bakalkin et al, 1980;Chazov et al, 1981;Bakalkin and Kobylyansky, 1989;Pilyavskii et al, 2013;Watanabe et al, 2020). The left hindlimb was flexed after administration of the µ-/ -agonist Met-enkephalin, and the selective -agonists dynorphin and U-50488 (Bakalkin et al, 1980;Chazov et al, 1981;Bakalkin and Kobylyansky, 1989;Watanabe et al, 2020). Conversely, Leu-enkephalin, which acts through the -receptor, caused the right hindlimb flexion (Bakalkin et al, 1980;Chazov et al, 1981).…”

“…Some of these molecules may be involved in lateralized processes and produce side specific effects due to lateralization of their target receptors. Thus, the opioid peptides dynorphins are affected by both the left or right side injury (Hauser et al, 2005;Hussain et al, 2012;Kononenko et al, 2018), and may induce a side-specific response; i.e., flexion of the left hindlimb (Bakalkin et al, 1980;Chazov et al, 1981;Bakalkin and Kobylyansky, 1989;Watanabe et al, 2020).…”

“…Inhibition of this response by -antagonists could reverse the flexion side if other neurohormones that induce a response on the other (right) side are also activated by the TBI (Watanabe et al, 2020) . In contrast to this mechanism, the more local UBI may primarily affect the left or right sided neuronal circuits of the mirror-symmetric neural pathways that convey signals from the injured hemisphere to lumbar motoneurons.…”

“…Previous studies demonstrated that in animals with intact brains opioid peptides and synthetic opioids mimic the effects of a unilateral brain lesion by inducing HL-PA with flexion on the side that was determined by the type of opioid agonist administered (Bakalkin et al, 1980;Chazov et al, 1981;Bakalkin et al, 1986;Bakalkin and Kobylyansky, 1989;Watanabe et al, 2020;. The and -agonists induced flexion of the left and right hindlimb, respectively.…”