scholarly journals Pathophysiological implication of CaV3.1 T-type Ca2+ channels in trigeminal neuropathic pain

2016 ◽  
Vol 113 (8) ◽  
pp. 2270-2275 ◽  
Author(s):  
Soonwook Choi ◽  
Eunah Yu ◽  
Eunjin Hwang ◽  
Rodolfo R. Llinás
Keyword(s):  
Neuropathic Pain ◽  
Somatosensory Cortex ◽  
Sensory Processing ◽  
Knockout Mice ◽  
Low Frequency ◽  
Infraorbital Nerve ◽  
Primary Somatosensory Cortex ◽  
Wild Type ◽  
Neuropathic Pain Syndrome ◽  
Trigeminal Neuropathic Pain

A crucial pathophysiological issue concerning central neuropathic pain is the modification of sensory processing by abnormally increased low-frequency brain rhythms. Here we explore the molecular mechanisms responsible for such abnormal rhythmicity and its relation to neuropathic pain syndrome. Toward this aim, we investigated the behavioral and electrophysiological consequences of trigeminal neuropathic pain following infraorbital nerve ligations in CaV3.1 T-type Ca2+ channel knockout and wild-type mice. CaV3.1 knockout mice had decreased mechanical hypersensitivity and reduced low-frequency rhythms in the primary somatosensory cortex and related thalamic nuclei than wild-type mice. Lateral inhibition of gamma rhythm in primary somatosensory cortex layer 4, reflecting intact sensory contrast, was present in knockout mice but severely impaired in wild-type mice. Moreover, cross-frequency coupling between low-frequency and gamma rhythms, which may serve in sensory processing, was pronounced in wild-type mice but not in CaV3.1 knockout mice. Our results suggest that the presence of CaV3.1 channels is a key element in the pathophysiology of trigeminal neuropathic pain.

scholarly journals Trigeminal Nerve Injury ErbB3/ErbB2 Promotes Mechanical Hypersensitivity

2012 ◽  
Vol 117 (2) ◽  
pp. 381-388 ◽  
Author(s):  
Fei Ma ◽  
Liping Zhang ◽  
Karin N. Westlund
Keyword(s):  
Neuropathic Pain ◽  
Nerve Injury ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Wild Type ◽  
Transgenic Rats ◽  
Neuregulin 1 ◽  
Mechanical Hypersensitivity ◽  
Trigeminal Neuropathic Pain ◽  
Whisker Pad

Background Chronic constriction injury of the trigeminal infraorbital nerve results in transient analgesia followed by whisker pad mechanical allodynia in rats. Neuregulin 1 expressed on axonal membranes binds receptor tyrosine kinase ErbB, promoting Schwann cell development and remyelination. This study investigated whether orofacial mechanical allodynia is signaled by ErbB3-ErbB2 heterodimers in injured nerves. Methods Whisker pad mechanical allodynia (von Frey stimuli) was quantified in wild type rats and in transgenic rats with Sleeping Beauty transposon mutation for neuregulin 1 transgene. Pain-related behavior was retested after intraperitoneal injection of the ErbB2 inhibitor Lapatinib, an agent shown by others to reduce breast cancer pain. Infraorbital nerve injury was evaluated histologically with myelin and neuronal biomarkers. ErbB3 changes over time were measured with western blots. Results Whisker pad mechanical hypersensitivity began in week 2 in wild type rats (3.11 ± 5.93 g vs. 18.72 ± 0.00 g after sham surgery, n = 9, P < 0.001), indicating trigeminal neuropathic pain, but was not evident in transgenic rats (odds ratio: 1.12, 95% confidence interval: 0.38-3.35). Initiation of statistically significant mechanohypersensitivity was delayed until week 6 after surgery in transgenic rats (3.44 ± 4.60 g vs. 18.72 ± 0.00 g, n = 4, P < 0.001). Mechanical allodynia, which persisted 8 weeks in wild type rats was alleviated by Lapatinib (15 ± 3.89 g vs. 2.45 ± 1.13 g, n = 6, P < 0.001). Infraorbital nerve damage was verified histologically. Statistically significant ErbB3 increases (weeks 5 and 10) in wild type and transgenic rats (week 10) coincided with time points when mechanical hypersensitivity was present. Conclusion The Neuregulin 1-ErbB3-ErbB2 complex is a causal mechanism in nerve injury-induced trigeminal neuropathic pain. Understanding peripheral glial mechanisms after nerve injury will improve neuropathic pain treatment.

scholarly journals Layer-specific sensory processing impairment in the primary somatosensory cortex after motor cortex infarction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Atsushi Fukui ◽  
Hironobu Osaki ◽  
Yoshifumi Ueta ◽  
Kenta Kobayashi ◽  
Yoshihiro Muragaki ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Somatosensory Cortex ◽  
Sensory Processing ◽  
Primary Somatosensory Cortex

scholarly journals TLR8 in the trigeminal ganglion contributes to the maintenance of trigeminal neuropathic pain

2020 ◽  
Author(s):  
Lin-Xia Zhao ◽  
Xue-Qiang Bai ◽  
De-Li Cao ◽  
Xiao-Bo Wu ◽  
Ming Jiang ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Trigeminal Ganglion ◽  
Proinflammatory Cytokines ◽  
Facial Pain ◽  
Calcium Concentration ◽  
Infraorbital Nerve ◽  
Rt Pcr ◽  
Pain Hypersensitivity ◽  
Trigeminal Neuropathic Pain ◽  
Significant Health

Abstract Background: Trigeminal neuropathic pain (TNP) is a significant health problem whereas the involved mechanism has not been completely elucidated. Toll-like receptors (TLRs) are recently demonstrated to be expressed in the dorsal root ganglion and involved in chronic pain. How TLR8 is expressed in the trigeminal ganglion (TG) after infraorbital nerve injury and whether TLR8 is involved in TNP have not been investigated.Methods: TNP model was established by the partial infraorbital nerve ligation (pIONL) in mice. The effect of TLR8 and its agonist VTX-2337 on pain hypersensitivity was checked by facial pain behavioral test. The immunostaining, real-time RT-PCR, and western blot were used to evaluate the expression of TLR8, pERK, pp38, and proinflammatory cytokines in the TG. The intracellular concentration of Ca 2+ was detected by the calcium imaging.Results: TLR8 was persistently increased in TG neurons in pIONL-induced TNP model. In addition, deletion of Tlr8 or knockdown of Tlr8 in the TG attenuated pIONL-induced mechanical allodynia, reduced the activation of ERK and p38, and decreased the expression of proinflammatory cytokines in the TG. Furthermore, intra-TG injection of TLR8 agonist VTX-2337 induced facial pain hypersensitivity. VTX-2337 also increased intracellular calcium concentration, induced activation of ERK and p38, and increased the proinflammatory cytokines expression in the TG.Conclusions: TLR8 contributes to the maintenance of TNP through increasing MAPK-mediated neuroinflammation. Targeting TLR8 signaling may be effective for the treatment of TNP.

Alleviation of trigeminal neuropathic pain by electroacupuncture: the role of hyperpolarization-activated cyclic nucleotide-gated channel protein expression in the Gasserian ganglion

2019 ◽  
Vol 37 (3) ◽  
pp. 192-198
Author(s):  
Liuyue Yang ◽  
Weihua Ding ◽  
Zerong You ◽  
Jinsheng Yang ◽  
Shiqian Shen ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Protein Expression ◽  
Cyclic Nucleotide ◽  
Mechanical Allodynia ◽  
Infraorbital Nerve ◽  
Gasserian Ganglion ◽  
Sprague Dawley ◽  
Trigeminal Neuropathic Pain ◽  
Sprague Dawley Rats ◽  
Gated Channel

Introduction: The aim of this study was to examine the effect of electroacupuncture (EA) on trigeminal neuropathic pain in rats and explore the potential mechanism underlying the putative therapeutic effect of EA. Methods: Trigeminal neuropathic pain behavior was induced in rats by unilateral chronic constriction injury of the distal infraorbital nerve (dIoN-CCI). EA was administered at ST2 ( Sibai) and Jiachengjiang. A total of 60 Sprague Dawley rats were divided into the following four groups ( n = 15 per group) to examine the behavioral outcomes after surgery and/or EA treatment: sham (no ligation); dIoN-CCI (received isoflurane only, without EA treatment); dIoN-CCI+EA-7d (received EA treatment for 7 days); and dIoN-CCI+EA-14d (received EA treatment for 14 days). Both evoked and spontaneous nociceptive behaviors were measured. Of these, 12 rats ( n = 4 from sham, dIoN-CCI, and dIoN-CCI+EA-14d groups, respectively) were used to analyze protein expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channel in the Gasserian ganglion (GG) by immunohistochemistry. Results: dIoN-CCI rats exhibited mechanical allodynia and increased face-grooming activity that lasted at least 35 days. EA treatment reduced mechanical allodynia and face-grooming in dIoN-CCI rats. Overall, 14 days of EA treatment produced a prolonged anti-nociceptive effect as compared to 7-day EA treatment. The counts of HCN1 and HCN2 immunopositive puncta were increased in the ipsilateral GG in dIoN-CCI rats and were reduced by 14 days of EA treatment. Discussion: EA treatment relieved trigeminal neuropathic pain in dIoN-CCI rats, and this effect was dependent on the duration of EA treatment. The downregulation of HCN expression may contribute to the anti-nociceptive effect of EA in this rat model of trigeminal neuropathic pain.

scholarly journals Distinct nociresponsive region in mouse primary somatosensory cortex

2021 ◽  
Author(s):  
Hironobu Osaki ◽  
Moeko Kanaya ◽  
Yoshifumi Ueta ◽  
Mariko Miyata
Keyword(s):  
Neuropathic Pain ◽  
Somatosensory Cortex ◽  
Single Neuron ◽  
Simultaneous Recording ◽  
Primary Somatosensory Cortex ◽  
Tactile Information ◽  
Tactile Input ◽  
Layer 2 ◽  
Nociceptive Processing ◽  
Nociceptive Information

Nociception, somatic discriminative aspects of pain, is represented in the primary somatosensory cortex (S1), as is touch, but the separation and the interaction of the two modalities within S1 remain unclear. Here, we show the spatially-distinct tactile and nociceptive processing in the granular barrel field (BF) and the adjacent dysgranular region (Dys) in mouse S1. Simultaneous recording of the multiunit activity across subregions reveals that Dys responses are selective to noxious input whereas those of BF are to tactile input. At the single neuron level, nociceptive information is represented separately from the tactile information in Dys layer 2/3. In contrast, both modalities are converged in a layer 5 neuron in each region. Interestingly, the two modalities interfere with each other in both regions. We further demonstrate that Dys, but not BF, activity is critically involved in neuropathic pain and pain behavior, and thus provide evidence that Dys is a center specialized for nociception in S1.

scholarly journals Layer-specific sensory processing impairment in the primary somatosensory cortex after motor cortex infarction

2019 ◽  
Author(s):  
Atsushi Fukui ◽  
Hironobu Osaki ◽  
Yoshifumi Ueta ◽  
Yoshihiro Muragaki ◽  
Takakazu Kawamata ◽  
...  
Keyword(s):  
Motor Cortex ◽  
Somatosensory Cortex ◽  
Acute Phase ◽  
Sensory Processing ◽  
Primary Motor Cortex ◽  
Temporal Coding ◽  
Network Activity ◽  
Primary Somatosensory Cortex ◽  
Inhibitory Input ◽  
Sensory Impairment

AbstractPrimary motor cortex (M1) infarction occasionally causes sensory impairment. Because sensory signal plays an important role in motor control, sensory impairment compromises recovery and rehabilitation from motor disability. Despite the importance of sensory-motor integration for rehabilitation after M1 infarction, the neural mechanism of the sensory impairment is poorly understood. We show that the sensory processing in the primary somatosensory cortex (S1) was impaired in the acute phase of M1 infarction and recovered in a layer-specific manner in the subacute phase. This layer dependent recovery process and the anatomical connection pattern from M1 to S1 suggested the functional connectivity from M1 to S1 plays a key role in the impairment of sensory processing in S1. The simulation study demonstrated that the loss of inhibition from M1 to S1 in the acute phase of M1 infarction could cause the sensory processing impairment in S1, and the complementation of inhibition could recover the temporal coding. Taken together, we revealed how focal stroke of M1 alters cortical network activity of sensory processing, in which inhibitory input from M1 to S1 may be involved.

Comparative analysis of labile and stable high-frequency TENS in the treatment of neuropathic pain syndrome

2021 ◽  
pp. 40-46
Author(s):  
M. Kh. Al-Zamil
Keyword(s):  
Neuropathic Pain ◽  
Comparative Analysis ◽  
High Frequency ◽  
Analgesic Effect ◽  
Low Frequency ◽  
Lower Extremities ◽  
Pain Syndrome ◽  
Neuropathic Pain Syndrome ◽  
Reduction Of Pain

Introduction: There have been many works devoted to the comparative analysis of high-frequency and low-frequency TENS in the treatment of neuropathic pain syndrome. Meanwhile, the comparative analysis of the methods of labile and stable TENS has not been sufficiently studied to date. Purpose: To make a comparative analysis of labile and stable high-frequency TENS in the treatment of neuropathic pain syndrome in patients with distal polyneuropathy of the lower extremities (DPLE). Materials and methods: 64 patients (F: 34, M: 30) with severe neuropathic pain syndrome on the background of diabetic DPLE were studied. Depending on the method of high-frequency TENS, all patients were divided into 2groups: stable high-frequency TENS (n=31) and labile high-frequency TENS (n=33). TENS was carried out every other day for a month. The severity of pain was determined by the VAS before each procedure. Results: The reduction of pain syndrome with the use of labile stimulation was 76.9%, compared to stable stimulation — 41,6%. With daily registration of pain syndrome, a significant increase in pain syndrome was revealed in patients who underwent stable high-frequency TENS after the 7th procedure to 4,5±0,3points in comparison with the indicators of pain syndrome obtained after the 3rd procedure (3,2±0,14). Conclusions: The analgesic effect of the labile high-frequency TENS significantly exceeds the analgesic effect of the stable high-frequency TENS by 85.1%. Partial tolerance to high-frequency TENS is observed when applying stable stimulation, which develops after the 7th procedure and is not observed after labile TENS.

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