Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord

Кононенко, О.; Mityakina, Irina; Galatenko, Vladimir; Watanabe, Hiroyuki; Bazov, Igor; Геращенко, А. В.; Sarkisyan, Daniil; Iatsyshyna, A. P.; Yakovleva, Tatiana; Tonevitsky, Alex; Marklund, Niklas; Ossipov, Michael H.; Bakalkin, Georgy

doi:10.1016/j.brainres.2018.05.043

Cited by 19 publications

(22 citation statements)

References 52 publications

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“…Besides left–right differences in segmental reflexes ( Hultborn and Malmsten, 1983 a , b ; Malmsten, 1983 ; and this study), physiological, anatomical and molecular asymmetries in the spinal cord ( Bakalkin et al , 1980 ; Chazov et al , 1981 ; Bakalkin et al , 1986 ; Bakalkin and Kobylyansky, 1989 ; Nathan et al , 1990 ; de Kovel et al , 2017 ; Kononenko et al , 2017 ; Ocklenburg et al , 2017 ; Kononenko et al , 2018 ; Woytowicz et al , 2018 ) along with general lateralization of motor functions ( Sainburg, 2014 ; Sainburg et al , 2016 ; Knebel et al , 2018 ; Stancher et al , 2018 ) have been reported. Three-quarters of cervical spinal cords are asymmetric with larger right side ( Nathan et al , 1990 ).…”

Section: Discussionsupporting

confidence: 61%

“…The rats were sacrificed by decapitation on Day 3 after the injury, the lumbar spinal cords were dissected into the left and right halves. RNA purification, quality evaluation, cDNA synthesis and quantitative RT-PCR were described elsewhere ( Kononenko et al , 2018 ). mRNA levels of 13 neuroplastic genes ( Supplementary Table 2 ) were normalized to geometric mean of expression levels of two control genes Actb and Gapdh .…”

Section: Methodsmentioning

confidence: 99%

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Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry

Zhang

Watanabe

Sarkisyan

et al. 2020

Brain Communications

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131

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Mechanisms of motor deficits (e.g. hemiparesis and hemiplegia) secondary to stroke and traumatic brain injury remain poorly understood. In early animal studies, a unilateral lesion to the cerebellum produced postural asymmetry with ipsilateral hindlimb flexion that was retained after complete spinal cord transection. Here we demonstrate that hindlimb postural asymmetry in rats is induced by a unilateral injury of the hindlimb sensorimotor cortex, and characterize this phenomenon as a model of spinal neuroplasticity underlying asymmetric motor deficits. After cortical lesion, the asymmetry was developed due to the contralesional hindlimb flexion and persisted after decerebration and complete spinal cord transection. The asymmetry induced by the left-side brain injury was eliminated by bilateral lumbar dorsal rhizotomy, but surprisingly, the asymmetry after the right-side brain lesion was resistant to deafferentation. Pancuronium, a curare-mimetic muscle relaxant, abolished the asymmetry after the right-side lesion suggesting its dependence on the efferent drive. The contra- and ipsilesional hindlimbs displayed different musculo-articular resistance to stretch after the left but not right-side injury. The nociceptive withdrawal reflexes evoked by electrical stimulation and recorded with EMG technique were different between the left and right hindlimbs in the spinalized decerebrate rats. On this asymmetric background, a brain injury resulted in greater reflex activation on the contra- versus ipsilesional side; the difference between the limbs was higher after the right-side brain lesion. The unilateral brain injury modified expression of neuroplasticity genes analysed as readout of plastic changes, as well as robustly impaired coordination of their expression within and between the ipsi- and contralesional halves of lumbar spinal cord; the effects were more pronounced after the left side compared to the right-side injury. Our data suggest that changes in the hindlimb posture, resistance to stretch and nociceptive withdrawal reflexes are encoded by neuroplastic processes in lumbar spinal circuits induced by a unilateral brain injury. Two mechanisms, one dependent on and one independent of afferent input may mediate asymmetric hindlimb motor responses. The latter, deafferentation resistant mechanism may be based on sustained muscle contractions which often occur in patients with central lesions and which are not evoked by afferent stimulation. The unusual feature of these mechanisms is their lateralization in the spinal cord.

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Section: Discussionsupporting

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry

Zhang

Watanabe

Sarkisyan

et al. 2020

Brain Communications

Self Cite

131

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“…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).…”

Section: Discussionmentioning

confidence: 99%

“…The raw qRT-qPCR data were obtained by the CFX Maestro™ Software for CFX384 Touch™ Real-Time PCR Detection System (Bio-Rad Laboratories, CA, USA). The mRNA levels of genes of interest were normalized to the geometric mean of expression levels of two reference genes Actb and Gapdh selected out of 10 genes (Actb,B2m,Gapdh,Gusb,Hprt,Pgk,Ppia,Rplpo13a,Tbp,and Tfrc), using the geNorm program (https://genorm.cmgg.be/ and (Vandesompele et al, 2002;Kononenko et al, 2017;Kononenko et al, 2018)). The expression stability of candidate reference genes was computed for ten sets of samples that were the left and right halves of the lumbar spinal cord obtained from intact rats, left-and right-sided sham surgery groups, and the left-and right-sided UBI groups, and was as follows (from high to low): Actb, Gapdh,Tbp,Rplpo13a,Hprt,Pgk,B2m,Tfrc,Ppia,and Gusb. In each experiment, the internal reference gene-stability measure M value did not exceed the 1.5 threshold value imposed by the MIQE.…”

Section: Quantitative Rt-pcrmentioning

confidence: 99%

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

Watanabe

Nosova

Sarkisyan

et al. 2021

eNeuro

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“…According to the GTEx, all the SNPs near OPRK1 with suggestive association with MC (see online supplementary table) are eQTLs for this gene. The protein encoded by the gene is an opioid receptor involved in pain perception, and variation in its expression is observed in the lumbar spinal cord in neuropathic pain model 45. Moreover, it is highly expressed in prechondrocytes and involved in protection against degradation in injured cartilaginous tissues 46…”

Section: Discussionmentioning

confidence: 99%

Genome-wide meta-analysis identifies genetic locus on chromosome 9 associated with Modic changes

et al. 2019

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BackgroundLow back pain (LBP) is a common disabling condition. Lumbar disc degeneration (LDD) may be a contributing factor for LBP. Modic change (MC), a distinct phenotype of LDD, is presented as a pathological bone marrow signal change adjacent to vertebral endplate on MRI. It is strongly associated with LBP and has heritability around 30%. Our objective was to identify genetic loci associated with MC using a genome-wide meta-analysis.MethodsPresence of MC was evaluated in lumbar MRI in the Northern Finland Birth Cohort 1966 (n=1182) and TwinsUK (n=647). Genome-wide association analyses were carried out using linear regression model. Inverse-variance weighting approach was used in the meta-analysis.ResultsA locus associated with MC (p<5e-8) was found on chromosome 9 with the lead SNP rs1934268 in an intron of the PTPRD gene. It is located in the binding region of BCL11A, SPI1 and PBX3 transcription factors. The SNP was nominally associated with LBP in TwinsUK (p=0.001) but not associated in the UK Biobank (p=0.914). Suggestive signals (p<1e-5) were identified near XKR4, SCIN, MGMT, DLG2, ZNF184 and OPRK1.Conclusion PTPRD is a novel candidate gene for MC that may act via the development of cartilage or nervous system; further work is needed to define the mechanisms underlying the pathways leading to development of MC. This is the first genome-wide meta-analysis of MC, and the results pave the way for further studies on the genetic factors underlying the various features of spine degeneration and LBP.

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Differential effects of left and right neuropathy on opioid gene expression in lumbar spinal cord

Cited by 19 publications

References 52 publications

Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry

Hindlimb motor responses to unilateral brain injury: spinal cord encoding and left-right asymmetry

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

Genome-wide meta-analysis identifies genetic locus on chromosome 9 associated with Modic changes

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