1 INTRODUCTION

Traumatic brain injury (TBI) causes structural damage to multiple brain regions leading to sensorimotor impairments such as muscle weakness, spasticity and contractions (Feldman & Levin, 2016; Jamal, Leplaideur, Rousseau, Chochina, Moulinet-Raillon & Bonan, 2018; Roelofs, van Heugten, de Kam, Weerdesteyn & Geurts, 2018; Wilson et al., 2017). A unilateral TBI of cortical and subcortical structures often result in the formation of postural asymmetry with contralateral motor deficits including hemiplegia and hemiparesis (Jamal, Leplaideur, Rousseau, Chochina, Moulinet-Raillon & Bonan, 2018; Roelofs, van Heugten, de Kam, Weerdesteyn & Geurts, 2018; Wilson et al., 2017). Motor impairment on the affected side contributes to dynamic control asymmetry in favor of the less affected leg, weight-bearing asymmetry and impaired body sway control. The TBI-induced motor impairments are defined as the loss of symmetrical limb reflexes and functions, and a loss of pre-injury abilities. Along with the reinstatement of pre-injury patterns, the symmetric pattern of limb functions and sensorimotor reflexes is used as a measure of functional recovery (Fujimoto, Longhi, Saatman, Conte, Stocchetti & McIntosh, 2004; Schallert, Fleming, Leasure, Tillerson & Bland, 2000). Neuroplastic rearrangements in supraspinal and spinal neurocircuitries induced by aberrant asymmetric activity of descending neural tracts may underlie motor impairments. In contrast to adaptive changes in the brain, knowledge on the brain injury-induced spinal neuroplasticity is limited (Grau, 2014; Sist, Fouad & Winship, 2014; Tan, Chakrabarty, Kimura & Martin, 2012; Wolpaw, 2012).
Spinal cord neuroplasticity or “pathological spinal memory” was proposed as a mechanism of motor impairment after injury to the cerebellum (Chamberlain, Halick & Gerard, 1963; DiGiorgio, 1929). In these studies, a unilateral cerebellar lesion caused asymmetric hindlimb posture with flexion of the ipsilesional limb that persisted after complete spinal transection. Consistently, changes in spinal reflexes induced by lateral spinal cord lesion were found to retain after complete spinal transection, and paralleled by asymmetry in locomotion (Frigon, Barriere, Leblond & Rossignol, 2009; Rossignol & Frigon, 2011). Hindlimb postural asymmetry (HL-PA) was also induced by a large unilateral brain lesion (Varlinskaia, Rogachii, Klement’ev & Vartanian, 1984) and the localized focal lesion of the hindlimb representation area of the sensorimotor cortex (Bakalkin et al., 2018; Zhang, Watanabe, Sarkisyan, Thelin, Schouenborg & Bakalkin, 2018). The HL-PA was manifested as differences in the position of the ipsi- and contralesional hindlimbs. In contrast to cerebellar or lateral spinal cord injuries, the contralesional hindlimb was flexed. Formation of HL-PA with contralesional flexion correlated with motor deficits of the same limb (Bakalkin et al., 2018; Zhang, Watanabe, Sarkisyan, Thelin, Schouenborg & Bakalkin, 2018), and asymmetry of the hindlimb nociceptive withdrawal reflexes. The cortical injury also modified gene expression in the ipsi- and contralesional halves of lumbar spinal cord, and impaired coordination of gene expression between these halves. Thus, asymmetric changes in the hindlimb posture and nociceptive withdrawal reflexes may be encoded by molecular processes in lumbar spinal circuits. Overall the postural symmetry phenomenon recapitulates symptoms of asymmetric motor deficits observed in human subjects. Furthermore, it represents a promising translational animal model to unravel spinal mechanisms of unilateral motor deficits such as hemiplegia and hemiparesis and to identify pharmacological targets to interfere with a “pathological spinal memory trace”. The employment of this model for pharmacological purposes thus far has been limited by the absence of data on whether a clinically relevant brain injury e.g. a focal, unilateral TBI may induce the same phenomenon, and on spinal neurotransmitter systems mediating effects of brain injury on asymmetry formation.
The endogenous opioid system includes µ-, δ- and κ-opioid receptors and endogenous opioid peptides endorphins, enkephalins and dynorphins. Opioid receptors are expressed in dorsal and ventral spinal domains and involved in regulation of sensory processes and motor functions (Clarke, Galloway, Harris, Taylor & Ford, 1992; Steffens & Schomburg, 2011; Wang et al., 2018). Opioid peptides and synthetic opioid agonists may induce HL-PA in intact rats thus mimicking effects of a unilateral brain lesion (Bakalkin & Kobylyansky, 1989; Chazov, Bakalkin, Yarigin, Trushina, Titov & Smirnov, 1981). Unusual was the left-right side specificity of the effects; bremazocine and dynorphin, the -agonists and Met-enkephalin, the endogenous µ-/δ-agonist induced flexion of the left hindlimb, whereas Leu-enkephalin, a δ-agonist caused the right limb to flex.
In this study, we examined whether a unilateral controlled cortical impact (CCI) delivered on the sensorimotor cortex, a model of clinical focal TBI, induces HL-PA as a readout of asymmetric functional impairments; whether HL-PA is encoded at the spinal level, and whether the CCI-induced development of HL-PA and its fixation is mediated through opioid receptors.