Optogenetic stimulation of the motor cortex alleviates neuropathic pain in rats of infraorbital nerve injury with/without CGRP knock-down

Abstract Background Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear. Objective The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury. Methods Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively. Results We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition. Conclusion Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

Download Full-text

Optogenetic Stimulation of The Motor Cortex Alleviates Neuropathic Pain in Rats of Infraorbital Nerve Injury With/Without CGRP Knock-Down

10.21203/rs.3.rs-48555/v1 ◽

2020 ◽

Author(s):

Jaisan Islam ◽

Elina KC ◽

Byeong Ho Oh ◽

Soochong Kim ◽

Sang-hwan Hyun ◽

...

Keyword(s):

Neuropathic Pain ◽

Motor Cortex ◽

Trigeminal Neuralgia ◽

Trigeminal Ganglion ◽

Primary Motor Cortex ◽

Infraorbital Nerve ◽

Motor Cortex Stimulation ◽

Trigeminal Neuropathic Pain ◽

Optogenetic Stimulation ◽

Stimulation Of

Abstract Background: Previous studies have reported that electrical stimulation of the motor cortex is effective in reducing trigeminal neuropathic pain; however, the effects of optical motor cortex stimulation remain unclear. Objective: The present study aimed to investigate whether optical stimulation of the primary motor cortex can modulate chronic neuropathic pain in rats with infraorbital nerve constriction injury.Methods: Animals were randomly divided into a trigeminal neuralgia group, a sham group, and a control group. Trigeminal neuropathic pain was generated via constriction of the infraorbital nerve and animals were treated via selective inhibition of calcitonin gene-related peptide in the trigeminal ganglion. We assessed alterations in behavioral responses in the pre-stimulation, stimulation, and post-stimulation conditions. In vivo extracellular recordings were obtained from the ventral posteromedial nucleus of the thalamus, and viral and α-CGRP expression were investigated in the primary motor cortex and trigeminal ganglion, respectively.Results: We found that optogenetic stimulation significantly improved pain behaviors in the trigeminal neuralgia animals and it provided more significant improvement with inhibited α-CGRP state than active α-CGRP state. Electrophysiological recordings revealed decreases in abnormal thalamic firing during the stimulation-on condition.Conclusion: Our findings suggest that optical motor cortex stimulation can alleviate pain behaviors in a rat model of trigeminal neuropathic pain. Transmission of trigeminal pain signals can be modulated via knock-down of α-CGRP and optical motor cortex stimulation.

Download Full-text

Pre-motor versus motor cerebral cortex neuromodulation for chronic neuropathic pain

Scientific Reports ◽

10.1038/s41598-021-91872-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Igor Lavrov ◽

Timur Latypov ◽

Elvira Mukhametova ◽

Brian Lundstrom ◽

Paola Sandroni ◽

...

Keyword(s):

Neuropathic Pain ◽

Cerebral Cortex ◽

Motor Cortex ◽

Initial Assessment ◽

Motor Cortex Stimulation ◽

Chronic Neuropathic Pain ◽

Long Term Effect ◽

Stimulation Of

AbstractElectrical stimulation of the cerebral cortex (ESCC) has been used to treat intractable neuropathic pain for nearly two decades, however, no standardized approach for this technique has been developed. In order to optimize targeting and validate the effect of ESCC before placing the permanent grid, we introduced initial assessment with trial stimulation, using a temporary grid of subdural electrodes. In this retrospective study we evaluate the role of electrode location on cerebral cortex in control of neuropathic pain and the role of trial stimulation in target-optimization for ESCC. Location of the temporary grid electrodes and location of permanent electrodes were evaluated in correlation with the long-term efficacy of ESCC. The results of this study demonstrate that the long-term effect of subdural pre-motor cortex stimulation is at least the same or higher compare to effect of subdural motor or combined pre-motor and motor cortex stimulation. These results also demonstrate that the initial trial stimulation helps to optimize permanent electrode positions in relation to the optimal functional target that is critical in cases when brain shift is expected. Proposed methodology and novel results open a new direction for development of neuromodulation techniques to control chronic neuropathic pain.

Download Full-text

Analgesic effects of repetitive transcranial magnetic stimulation of the motor cortex in neuropathic pain: Influence of theta burst stimulation priming

European Journal of Pain ◽

10.1002/j.1532-2149.2012.00150.x ◽

2012 ◽

Vol 16 (10) ◽

pp. 1403-1413 ◽

Cited By ~ 57

Author(s):

J.-P. Lefaucheur ◽

S.S. Ayache ◽

M. Sorel ◽

W.H. Farhat ◽

H.G. Zouari ◽

...

Keyword(s):

Neuropathic Pain ◽

Transcranial Magnetic Stimulation ◽

Motor Cortex ◽

Magnetic Stimulation ◽

Repetitive Transcranial Magnetic Stimulation ◽

Theta Burst Stimulation ◽

Burst Stimulation ◽

Analgesic Effects ◽

Theta Burst ◽

Stimulation Of

Download Full-text

Suppression of Superficial Microglial Activation by Spinal Cord Stimulation Attenuates Neuropathic Pain Following Sciatic Nerve Injury in Rats

International Journal of Molecular Sciences ◽

10.3390/ijms21072390 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2390

Author(s):

Masamichi Shinoda ◽

Satoshi Fujita ◽

Shiori Sugawara ◽

Sayaka Asano ◽

Ryo Koyama ◽

...

Keyword(s):

Spinal Cord ◽

Neuropathic Pain ◽

Electrical Stimulation ◽

Dorsal Horn ◽

Nerve Injury ◽

Spinal Cord Stimulation ◽

Microglial Activation ◽

In Vivo Optical Imaging ◽

Stimulation Of

We evaluated the mechanisms underlying the spinal cord stimulation (SCS)-induced analgesic effect on neuropathic pain following spared nerve injury (SNI). On day 3 after SNI, SCS was performed for 6 h by using electrodes paraspinally placed on the L4-S1 spinal cord. The effects of SCS and intraperitoneal minocycline administration on plantar mechanical sensitivity, microglial activation, and neuronal excitability in the L4 dorsal horn were assessed on day 3 after SNI. The somatosensory cortical responses to electrical stimulation of the hind paw on day 3 following SNI were examined by using in vivo optical imaging with a voltage-sensitive dye. On day 3 after SNI, plantar mechanical hypersensitivity and enhanced microglial activation were suppressed by minocycline or SCS, and L4 dorsal horn nociceptive neuronal hyperexcitability was suppressed by SCS. In vivo optical imaging also revealed that electrical stimulation of the hind paw-activated areas in the somatosensory cortex was decreased by SCS. The present findings suggest that SCS could suppress plantar SNI-induced neuropathic pain via inhibition of microglial activation in the L4 dorsal horn, which is involved in spinal neuronal hyperexcitability. SCS is likely to be a potential alternative and complementary medicine therapy to alleviate neuropathic pain following nerve injury.

Download Full-text

Optogenetic Stimulation Reduces Neuronal Nitric Oxide Synthase Expression After Stroke

Neurosurgery ◽

10.1093/neuros/nyz310_173 ◽

2019 ◽

Vol 66 (Supplement_1) ◽

Author(s):

Arjun Vivek Pendharkar ◽

Daniel L Smerin ◽

Lorenzo Gonzales ◽

Eric Wang ◽

Sabrina L Levy ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Motor Cortex ◽

Functional Recovery ◽

Neuronal Nitric Oxide Synthase ◽

Optogenetic Stimulation ◽

Oxide Synthase ◽

Nnos Expression ◽

Stimulation Of ◽

Nnos Inhibition

Abstract INTRODUCTION Poststroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of neurovascular response in acute stroke but its role in subacute recovery remains unclear. Here we investigate nNOS expression in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examine the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS. METHODS Transgenic Thy1-ChR2-YFP male mice (10-12 wk) were used. Stereotaxic surgery was performed to implant a fiber cannula in the cLCN and animals underwent intraluminal middle cerebral artery suture occlusion (30 min). Optogenetic stimulation began at poststroke (PD) day 5 and continued until PD14. Sensorimotor tests were used to assess behavioral recovery at PD4, 7, 10, and 14. At PD15, primary motor cortex from both ipsi- and contralesional motor cortex (iM1, cM1) were dissected. nNOS mRNA and protein levels were examined using quantitative polymerase chain reaction and western blot. In another set of studies, nNOS inhibitor ARL 17477 dihydrochloride (10 mg/kg, intraperitoneally) was administered daily between PD5-14 and functional recovery was evaluated using sensorimotor tests. RESULTS cLCN stimulated stroke mice demonstrated significant improvement in speed (cm/s) on the rotating beam task at PD10 and 14 day (P < .05, P < .001 respectively). nNOS mRNA and protein expression was significantly and selectively decreased in cM1 of cLCN stimulated mice (P < .05). The reduced nNOS expression in cM1 was negatively correlated with improved recovery (R2 = −0.839, Pearson P = .009). nNOS inhibitor-treated stroke mice exhibited a significant functional improvement in speed at PD10, when compared to stroke mice receiving vehicle (saline) (P < .05). CONCLUSION Our results suggest that nNOS may play a maladaptive role in poststroke recovery. Optogenetic stimulation of cLCN and systemic nNOS inhibition produce functional benefits after stroke.

Download Full-text

(−)-α-Bisabolol reduces nociception and trigeminal central sensitisation in acute orofacial neuropathic pain induced by infraorbital nerve injury

Life Sciences ◽

10.1016/j.lfs.2019.04.032 ◽

2019 ◽

Vol 227 ◽

pp. 122-128 ◽

Cited By ~ 3

Author(s):

L.T. Melo ◽

V. Panchalingam ◽

P. Cherkas ◽

A.R. Campos ◽

L. Avivi-Arber ◽

...

Keyword(s):

Neuropathic Pain ◽

Nerve Injury ◽

Infraorbital Nerve ◽

Central Sensitisation

Download Full-text

Arm movements induced by noninvasive optogenetic stimulation of the motor cortex in the common marmoset

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1903445116 ◽

2019 ◽

Vol 116 (45) ◽

pp. 22844-22850 ◽

Cited By ~ 10

Author(s):

Teppei Ebina ◽

Keitaro Obara ◽

Akiya Watakabe ◽

Yoshito Masamizu ◽

Shin-Ichiro Terada ◽

...

Keyword(s):

Motor Cortex ◽

Nonhuman Primates ◽

Arm Movements ◽

Common Marmoset ◽

Blue Laser ◽

Optogenetic Stimulation ◽

Long Duration ◽

The Common ◽

Forelimb Movements ◽

Stimulation Of

Optogenetics is now a fundamental tool for investigating the relationship between neuronal activity and behavior. However, its application to the investigation of motor control systems in nonhuman primates is rather limited, because optogenetic stimulation of cortical neurons in nonhuman primates has failed to induce or modulate any hand/arm movements. Here, we used a tetracycline-inducible gene expression system carrying CaMKII promoter and the gene encoding a Channelrhodopsin-2 variant with fast kinetics in the common marmoset, a small New World monkey. In an awake state, forelimb movements could be induced when Channelrhodopsin-2−expressing neurons in the motor cortex were illuminated by blue laser light with a spot diameter of 1 mm or 2 mm through a cranial window without cortical invasion. Forelimb muscles responded 10 ms to 50 ms after photostimulation onset. Long-duration (500 ms) photostimulation induced discrete forelimb movements that could be markerlessly tracked with charge-coupled device cameras and a deep learning algorithm. Long-duration photostimulation mapping revealed that the primary motor cortex is divided into multiple domains that can induce hand and elbow movements in different directions. During performance of a forelimb movement task, movement trajectories were modulated by weak photostimulation, which did not induce visible forelimb movements at rest, around the onset of task-relevant movement. The modulation was biased toward the movement direction induced by the strong photostimulation. Combined with calcium imaging, all-optical interrogation of motor circuits should be possible in behaving marmosets.

Download Full-text

Microglia–Astrocyte Communication via C1q Contributes to Orofacial Neuropathic Pain Associated with Infraorbital Nerve Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21186834 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6834

Author(s):

Sayaka Asano ◽

Yoshinori Hayashi ◽

Koichi Iwata ◽

Akiko Okada-Ogawa ◽

Suzuro Hitomi ◽

...

Keyword(s):

Neuropathic Pain ◽

Glial Fibrillary Acidic Protein ◽

Nerve Injury ◽

Fluorescence Intensity ◽

Time Window ◽

Infraorbital Nerve ◽

Nociceptive Neurons ◽

Mechanical Hypersensitivity ◽

Injury Causes ◽

Immunohistochemical Analyses

Trigeminal nerve injury causes a distinct time window of glial activation in the trigeminal spinal subnucleus caudalis (Vc), which are involved in the initiation and maintenance phases of orofacial neuropathic pain. Microglia-derived factors enable the activation of astrocytes. The complement component C1q, which promotes the activation of astrocytes, is known to be synthesized in microglia. However, it is unclear whether microglia–astrocyte communication via C1q is involved in orofacial neuropathic pain. Here, we analyzed microglia-astrocyte communication in a rat model with infraorbital nerve injury (IONI). The orofacial mechanical hypersensitivity induced by IONI was significantly attenuated by preemptive treatment with minocycline. Immunohistochemical analyses revealed that minocycline inhibited the increase in c-Fos immune-reactive (IR) cells and the fluorescence intensity of both Iba1 and glial fibrillary acidic protein (GFAP) in the Vc following IONI. Intracisternal administration of C1q caused orofacial mechanical hypersensitivity and an increase in the number of c-Fos-IR cells and fluorescence intensity of GFAP. C1q-induced orofacial mechanical hypersensitivity was completely abrogated by intracisternal administration of fluorocitrate. The present findings suggest that the enhancement in the excitability of Vc nociceptive neurons is produced by astrocytic activation via the signaling of C1q released from activated microglia in the Vc following IONI, resulting in persistent orofacial neuropathic pain.

Download Full-text

Relief of neuropathic pain by cell-specific manipulation of nucleus accumbens dopamine D1- and D2-receptor-expressing neurons

Molecular Brain ◽

10.1186/s13041-021-00896-2 ◽

2022 ◽

Vol 15 (1) ◽

Author(s):

Daisuke Sato ◽

Michiko Narita ◽

Yusuke Hamada ◽

Tomohisa Mori ◽

Kenichi Tanaka ◽

...

Keyword(s):

Chronic Pain ◽

Neuropathic Pain ◽

Nucleus Accumbens ◽

Sciatic Nerve ◽

Nerve Injury ◽

D2 Receptor ◽

D1 Receptor ◽

Cholinergic Interneurons ◽

Chronic Pain Conditions ◽

Stimulation Of

AbstractEmerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

Download Full-text