Yoshinori Terashima

Transient receptor potential ankyrin 1 in spinal cord dorsal horn is involved in neuropathic pain in nerve root constriction rats

BackgroundLumbar radicular pain is categorized as a type of neuropathic pain, but its pathophysiological mechanisms are not fully understood. The substantia gelatinosa (SG) in the spinal cord dorsal horn receives primary afferent inputs and is considered to be a therapeutic target for treating neuropathic pain. In vivo patch-clamp recording is a useful procedure for analyzing the functional properties of synaptic transmission in SG neurons. Transient receptor potential ankyrin 1 (TRPA1) has been widely identified in the central and peripheral nervous systems, such as in the peripheral nociceptor, dorsal root ganglion, and spinal cord dorsal horn and is involved in synaptic transmission of pain. However, its functional role and mechanism of pain transmission in the spinal cord dorsal horn are not well understood. The purpose of this study was to use in vivo patch-clamp analysis to examine changes in the excitatory synaptic transmission of SG neurons treated with TRPA1 antagonist and to clarify the potential role of TRPA1 in the rat spinal cord dorsal horn.ResultsThe rats with root constriction (RC) showed mechanical hypersensitivity, hyperalgesia, and thermal hyperalgesia. In addition, pin pricks elicited pain-related behavior even in the sham and naïve rats. These pain-related behaviors were significantly attenuated by intrathecal injection of a TRPA1 antagonist. The degrees of intrathecal injection efficacy were equivalent among the 3 groups (RC, sham, and naïve groups). In an electrophysiological study, the frequencies and amplitudes of excitatory postsynaptic currents (EPSCs) were significantly increased in the RC rats compared with those in the sham and naïve rats. Spontaneous EPSCs and evoked-EPSCs by non-noxious and noxious stimuli were significantly decreased by TRPA1 antagonist. As in the behavioral study, there were no statistically significant differences among the 3 groups.ConclusionThese data showed that the TRPA1 antagonist had an inhibitory effect on mechanical hypersensitivity and hyperalgesia as well as on physiological pain transmission in the spinal cord dorsal horn. This suggests that TRPA1 is consistently involved in excitatory synaptic transmission even in the physiological state and has a role in coordinating pain transmission.

Changes in synaptic transmission of substantia gelatinosa neurons in a rat model of lumbar radicular pain revealed by in vivo patch-clamp recording.

&NA; Little is known about the pathophysiological mechanisms of radicular pain. We investigated changes in synaptic transmission of substantia gelatinosa (SG) neurons after an injury to the L5 nerve root using in vivo patch‐clamp recording. A total of 141 SG neurons were recorded at L4 and L5 segmental levels of the spinal cord in root constriction rats and sham‐operated control rats. At L4 and L5 segmental levels, SG neurons without a receptive field were observed only in root constriction rats, and the frequencies of spontaneous action potential firings in SG neurons were higher in the root constriction group than in the control group. At the L5 segmental level, the frequencies and amplitudes of spontaneous excitatory postsynaptic currents (EPSCs) as well as the proportion of multireceptive neurons among SG neurons was higher in the root constriction group than in the control group. At the L4 segmental level, the frequencies and amplitudes of spontaneous EPSCs were increased in the root constriction group, but the proportions of cell types did not change. The mean amplitudes of EPSCs evoked by mechanical stimuli at L4 and L5 segmental levels were larger in the root constriction group than in the control group. The results indicated that injuring the nerve root led to characteristic excitatory synaptic transmission in SG neurons at each segmental level and changed sensory processing in SG neurons at the segment to which the injured nerve projected. These changes could lead to spontaneous pain, mechanical allodynia, and hyperalgesia contributing to the pathogenesis of radicular pain. Injuring the nerve root led to characteristic excitatory synaptic transmission and changed sensory processing in substantia gelatinosa neurons in the rat spinal dorsal horn.

Efficacy of diffusion-weighted magnetic resonance imaging in diagnosing spinal root disorders in lumbar disc herniation.

Study Design. Prospective study based on magnetic resonance imaging for lumbar disc herniation. Objective. In this study, we captured diffusion-weighted imaging (DWI) of dorsal root ganglion (DRG) of the affected nerve root in lumbar disc herniation and examined the relationship between apparent diffusion coefficient (ADC) and clinical symptoms to evaluate the efficacy of DWI in the diagnosis of lumbar spinal disorders. Summary of Background Data. DWI captures diffusion of water molecules in intracellular or extracellular fluid, allowing visualization of edematous changes, and is therefore used in diagnosis of hyper-acute cerebral infarction. In addition, it is possible to quantify the degree of diffusion using ADC calculated from the DWI data. Meanwhile in lumbar disc herniation, edematous changes occur in DRG of affected nerve root. If DWI enables visualization of these edematous changes, it will be possible to diagnose objectively the affected level. Methods. The subjects were 30 patients who underwent surgery of unilateral radiculopathy and a single level lumbar disc herniation. We analyzed the relationship between morbidity duration, visual analogue scale (VAS) score of leg symptoms, and ADC. In addition, we investigated any correlation between VAS recovery ratio (i.e., VAS preoperative − VAS postoperative)/VAS preoperative × 100) with ADC. Results. When compared with the contralateral side, ADC of the affected DRG was observed to increase in 18 and decrease in 12 subjects, and thus no definite trend was observed. The relationship between morbidity duration, VAS score, and ADC had no observed correlation. A positive correlation between ADC and VAS recovery ratio was statistically observed (P < 0.01, leg pain: r = 0.707, leg numbness: r = 0.738). Conclusion. This study showed that patients with decreased ADC tended to show poor improvement of leg symptoms, which may suggest the possibility that ADC of DRG is related to neuronal plasticity. Level of Evidence: 2

Sympathectomy attenuates excitability of dorsal root ganglion neurons and pain behaviour in a lumbar radiculopathy model

Objectives In order to elucidate the influence of sympathetic nerves on lumbar radiculopathy, we investigated whether sympathectomy attenuated pain behaviour and altered the electrical properties of the dorsal root ganglion (DRG) neurons in a rat model of lumbar root constriction. Methods Sprague-Dawley rats were divided into three experimental groups. In the root constriction group, the left L5 spinal nerve root was ligated proximal to the DRG as a lumbar radiculopathy model. In the root constriction + sympathectomy group, sympathectomy was performed after the root constriction procedure. In the control group, no procedures were performed. In order to evaluate the pain relief effect of sympathectomy, behavioural analysis using mechanical and thermal stimulation was performed. In order to evaluate the excitability of the DRG neurons, we recorded action potentials of the isolated single DRG neuron by the whole-cell patch-clamp method. Results In behavioural analysis, sympathectomy attenuated the mechanical allodynia and thermal hyperalgesia caused by lumbar root constriction. In electrophysiological analysis, single isolated DRG neurons with root constriction exhibited lower threshold current, more depolarised resting membrane potential, prolonged action potential duration, and more depolarisation frequency. These hyperexcitable alterations caused by root constriction were significantly attenuated in rats treated with surgical sympathectomy. Conclusion The present results suggest that sympathectomy attenuates lumbar radicular pain resulting from root constriction by altering the electrical property of the DRG neuron itself. Thus, the sympathetic nervous system was closely associated with lumbar radicular pain, and suppressing the activity of the sympathetic nervous system may therefore lead to pain relief.

Investigation of Intervertebral Disc and Facet Joint in Lumbar Spondylolisthesis using T2 Mapping

PURPOSE We measured T2 relaxation time of the intervertebral discs (IVD) and facet joints (FJ) in patients with degenerative spondylolisthesis (DS) and no spondylolisthesis (NS) and investigated the characteristics of these parts in DS. METHODS In 40 patients with DS and 40 patients with NS, we measured T2 relaxation time of the IVD and FJ and compared them between groups. In the group with DS, we also examined the relationship between the degree of slippage using Meyerding grade and T2 relaxation of each part in the IVD and FJ. RESULTS T2 relaxation time of the IVD tended to be lower in the DS than NS group and differed significantly (P < 0.01) within the anterior annulus fibrosus. T2 relaxation time in the FJ was significantly higher in the DS than NS group. T2 relaxation time in the FJ was significantly higher for those assessed Meyerding Grade II than Grade I, although we observed no significant differences in T2 relaxation time in any area of the IVD. CONCLUSION T2 relaxation time decreased in the anterior annulus fibrosus of the IVD and increased in the FJ in patients with DS, suggesting an association of IVD and FJ degeneration with the development of lumbar DS.

Evaluation of intramyocellular and extramyocellular lipids in the paraspinal muscle in patients with chronic low back pain using MR spectroscopy: preliminary results.

OBJECTIVE: To analyze the intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) in the psoas muscle (Pm) and multifidus muscle (Mm) using MR spectroscopy (MRS) in patients with chronic low back pain (CLBP) and asymptomatic volunteers. METHODS: This prospective study had institutional review board approval, and written informed consent was obtained from all individual participants. 20 patients with CLBP (mean age, 49.8 ± 12.5 years; age range, 28-66 years) with low back pain (LBP) duration of ≥3 months and asymptomatic volunteers (mean age, 44.0 ± 12.8 years; age range, 28-65 years) underwent MRS for the quantification of IMCL and EMCL of the right Pm and Mm in a volume of interest at the intervertebral level of L4 through L5. We compared patients with CLBP and asymptomatic volunteers for age and body mass index (BMI), IMCL and EMCL of Pm and Mm. The Mann-Whitney U-test was used for significant difference testing, with p-value <0.05 indicating statistical significance. RESULTS: No statistically significant differences were observed in the age and BMI of patients with CLBP and asymptomatic volunteers. There was no statistically significant difference in the EMCL and IMCL in Pm between the two groups. EMCL in Mm was not statistically significantly different; the IMCL of patients with CLBP was significantly higher than that of asymptomatic volunteers (p < 0.05). CONCLUSION: MRS demonstrates that IMCL in the Mm of patients with CLBP is significantly higher than that of asymptomatic volunteers. The increase of IMCL in the Mm may be a characteristic finding in CLBP. ADVANCES IN KNOWLEDGE: We investigated the detail of the fat content in the paraspinal muscles in patients CLBP and asymptomatic volunteers. The increase of fat content in the Mm of patients with LBP on previous studies was demonstrated to be the increase of IMCL.

Attenuation of pain behaviour by local administration of alpha-2 adrenoceptor antagonists to dorsal root ganglia in a rat radiculopathy model

There were several reports suggesting α‐adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of α‐adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved.

Sympathectomy and Sympathetic Blockade Reduce Pain Behavior Via Alpha-2 Adrenoceptor of the Dorsal Root Ganglion Neurons in a Lumbar Radiculopathy Model.

Study Design. Animal experimental study with intervention. Objective. We investigated whether sympathectomy and pharmacological sympathetic blockade reduced pain behavior and reversed adrenoceptor mRNA expression of the dorsal root ganglion (DRG) in a lumbar radiculopathy model. Summary of Background Data. The abnormal sympathetic-somatosensory interaction may underlie some forms of neuropathic pain. There are several reports that sympathectomy and pharmacological sympathetic blockades are often effective to treat neuropathic pain. However, its pathophysiological mechanisms remain obscure. Methods. We used 91 male Sprague-Dawley rats. Just after root constriction (RC), the rats underwent sympathectomy or received 3 local injections of subtype-specific &agr;-adrenergic receptor antagonists around the DRG. We evaluated the analgesic effects of sympathectomy and sympathetic blockade using behaviors indicative mechanical allodynia and thermal hyperalgesia. We estimated the mRNA expression levels of the DRG adrenoceptor subtypes using real time reverse transcription polymerase chain reaction. Results. Sympathectomy and &agr;2-antagonist significantly reduced the mechanical allodynia and thermal hyperalgesia after RC. Real time reverse transcription polymerase chain reaction analysis indicated that sympathectomy possibly reversed &agr;2A- and &agr;2B-adrenoceptors mRNA overexpression in the DRG after RC. Conclusion. We considered that pain behaviors of neuropathic pain are due, at least in part, to enhanced sympathetic noradrenergic transmission within the DRG. Suppression of sympathetic activity by reducing adrenergic release, &agr;2-adrenoceptor stimulation, and/or &agr;2-adrenoceptor upregulation in the DRG may relieve neuropathic pain. Level of Evidence: 3

Analysis of intra and extramyocellular lipids in the multifidus muscle in patients with chronic low back pain using MR spectroscopy

OBJECTIVE To analyse the intra- (IMCL) and extramyocellular lipids (EMCL) concentration in the multifidus muscle (Mm) using MR spectroscopy (MRS) in patients with low back pain (LBP), and to evaluate the correlation between those lipid concentrations and age, obesity, atrophy of the Mm and LBP intensity. METHODS 60 LBP patients underwent routine diagnostic MRI of the lumbar spine before undergoing imaging for the study. Body mass index, as an indicator of obesity and visual analogue scale, as an indicator of LBP were also measured. Proton MRS was acquired with a single-voxel point-resolved spectroscopy sequence. Furthermore, the MRS volume of interest for measuring the IMCL and EMCL concentration at L4/5 for the right Mm was determined, and we measured the cross-sectional area of Mm as an indicator of muscle atrophy. RESULTS Age showed correlation with EMCL concentration (r = 0.314, p = 0.008). The body mass index showed correlation with EMCL concentration (r = 0.358, p = 0.005). The cross-sectional area of Mm showed correlation with EMCL concentration (r = -0.543, p < 0.001). Moreover, the LBP visual analogue scale showed correlation with IMCL concentration (r = 0.367, p = 0.004). CONCLUSION There were correlations between age, obesity, muscle atrophy, and EMCL concentration in Mm. IMCL concentration in Mm showed a correlation with LBP intensity. This may suggest that IMCL concentration could become an effective objective indicator of chronic LBP intensity. Advances in knowledge: We investigated the characteristics of fat content in Mm with LBP patients. This study was demonstrated the association of the IMCL and EMCL concentration in Mm with various patient parameters.

Magnetic resonance spectroscopic analysis of multifidus muscles lipid content and association with spinopelvic malalignment in chronic low back pain

OBJECTIVE To analyze intramyocellular lipids (IMCLs) and extramyocellular lipids (EMCLs) of the multifidus muscle (Mm) using MR spectroscopy in chronic low back pain (CLBP) and control groups and to identify correlations with spinopelvic alignment. METHODS 40 patients (16 males, 24 females; mean age, 62.9 ± 1.9 years) whose visual analogue scale scores were >30 mm for CLBP were included. Furthermore, 40 control participants matched with the CLBP group subjects by sample size, gender and age (17 males, 23 females; mean age, 65.0 ± 1.2 years) were included. We compared the body mass index, physical workload, leisure time physical activity level, spinopelvic parameters, and IMCLs and EMCLs of the Mm between the groups. We also evaluated possible correlations of spinopelvic parameters with IMCLs and EMCLs of the Mm in the groups. RESULTS There were no statistically significant differences in body mass index, physical workload, exercise intensity level, spinopelvic parameters and EMCLs between the groups. The IMCLs were significantly higher in the CLBP group than in the control group (p < 0.01). In the CLBP group, there was a significantly negative correlation between IMCLs and lumbar lordosis (r = -0.64, p < 0.01) and a significantly positive correlation between IMCLs and sagittal vertical axis (r = 0.43, p < 0.01). CONCLUSION The measurement of IMCLs might be a characteristic finding of CLBP as well as a precursor to spinal deformity. Advances in knowledge: IMCLs of the Mm may be a useful prognostic marker in rehabilitation strategies for patients with CLBP.