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Abstract Trigeminal neuropathic pain (TNP) is a major concern in both dentistry and medicine. The progression from normal to chronic TNP through activation of the insular cortex (IC) is thought to involve several neuroplastic changes in multiple brain regions, resulting in distorted pain perception and associated comorbidities. While the functional changes in the insula are recognized contributors to TNP, the intricate mechanisms underlying the involvement of the insula in TNP processing remain subjects of ongoing investigation. Here, we have overviewed the most recent advancements regarding the functional role of IC in regulating TNP alongside insights into the IC’s connectivity with other brain regions implicated in trigeminal pain pathways. In addition, the review examines diverse modulation strategies that target the different parts of the IC, thereby suggesting novel diagnostic and therapeutic management of chronic TNP in the future.

Abstract The significance of hyperactive astrocytes in neuropathic pain is crucial. However, the association between medullary astrocytes and trigeminal neuralgia (TN)-related pain processing is unclear. Here, we examined how optogenetic inhibition of medullary astrocytes in the trigeminal nucleus caudalis (TNC) regulates pain hypersensitivity in an infraorbital nerve (ION) constricted TN model. We used adult Sprague Dawley rats subjected to infraorbital nerve (ION) constriction to mimic TN symptoms, with naive and sham rats serving as controls. For in vivo optogenetic manipulations, rats stereotaxically received AAV8-GFAP-eNpHR3.0-mCherry or AAV8-GFAP-mCherry at the trigeminal nucleus caudalis (TNC). Open field, von Frey, air puff, and acetone tests measured pain behavioral flexibility. In vivo thalamic recordings were obtained simultaneously with optogenetic manipulation in the TNC. Orofacial hyperalgesia and thalamic hyperexcitability were both accompanied by medullary astrocyte hyperactivity, marked by upregulated GFAP. The yellow laser-driven inhibition of TNC astrocytes markedly improved behavioral responses and regulated thalamic neuronal responses. Halorhodopsin-mediated inhibition in medullary astrocytes may modify the nociceptive input transmitted through the trigeminothalamic tract and pain perception. Taken together, these findings imply that this subpopulation in the TNC and its thalamic connections play a significant role in regulating the trigeminal pain circuitry, which might aid in the identification of new therapeutic measures in TN management. Graphical Abstract

Abstract Posterior hypothalamus (PH), an important part of the descending pain processing pathway, has been found to be activated in trigeminal autonomic cephalalgias. However, there are very few studies conducted and information regarding its implications in trigeminal neuropathic pain (TNP). Therefore, we aimed to ascertain whether optogenetic inhibition of PH could affect the outcomes of a chronic constriction injury in the infraorbital nerve (CCI-ION) rat model. Animals were divided into the TNP animal, sham, and naive-control groups. CCI-ION surgery was performed to mimic TNP symptoms, and the optogenetic or null virus was injected into the ipsilateral PH. In vivo single-unit extracellular recordings were obtained from both the ipsilateral ventrolateral periaqueductal gray (vlPAG) and contralateral ventral posteromedial (VPM) thalamus in stimulation “OFF” and “ON” conditions. Alterations in behavioral responses during the stimulation-OFF and stimulation-ON states were examined. We observed that optogenetic inhibition of the PH considerably improved behavioral responses in TNP animals. We found increased and decreased firing activity in the vlPAG and VPM thalamus, respectively, during optogenetic inhibition of the PH. Inhibiting PH attenuates trigeminal pain signal transmission by modulating the vlPAG and trigeminal nucleus caudalis, thereby providing evidence of the therapeutic potential of PH in TNP management.

Abstract Excruciating trigeminal neuralgia (TN) management is very difficult and severely affects the patient’s quality of life. Earlier studies have shown that the trigeminal ganglion (TG) comprises several receptors and signal molecules that are involved in the process of peripheral sensitization, which influences the development and persistence of neuropathic pain. Targeting TG can modulate this sensitization pathway and mediate the pain-relieving effect. So far,there are few studies in which modulation approaches to TG itself have been suggested so far. “Trigeminal ganglion modulation” and “trigeminal neuralgia” were used as search phrases in the Scopus Index and PubMed databases to discover articles that were pertinent to the topic. In this review, we address the role of the trigeminal ganglion in TN and underlying molecules and neuropeptides implicated in trigeminal pain pathways in processing pathological orofacial pain. We also reviewed different modulation approaches in TG for TN management. Furthermore, we discuss the prospect of targeting trigeminal ganglion to manage such intractable pain.

Abstract Background Human embryonic stem cells (hESCs) transplantation had shown to provide a potential source of cells in neurodegenerative disease studies and lead to behavioral recovery in lentivirus transfected or, toxin-induced Huntington's disease (HD) rodent model. Here, we aimed to observe if transplantation of superparamagnetic iron oxide nanoparticle (SPION)-labeled hESCs could migrate in the neural degenerated area and improve motor dysfunction in an AAV2-Htt171-82Q transfected Huntington rat model. Methods All animals were randomly allocated into three groups at first: HD group, sham group, and control group. After six weeks, the animals of the HD group and sham group were again divided into two subgroups depending on animals receiving either ipsilateral or contralateral hESCs transplantation. We performed cylinder test and stepping test every two weeks after AAV2-Htt171-82Q injection and hESCs transplantation. Stem cell tracking was performed once per two weeks using T2 and T2*-weighted images at 4.7 Tesla MRI. We also performed immunohistochemistry and immunofluorescence staining to detect the presence of hESCs markers, huntingtin protein aggregations, and iron in the striatum. Results After hESCs transplantation, the Htt virus-injected rats exhibited significant behavioral improvement in behavioral tests. SPION labeled hESCs showed migration with hypointense signal in MRI. The cells were positive with βIII-tubulin, GABA, and DARPP32. Conclusion Collectively, our results suggested that hESCs transplantation can be a potential treatment for motor dysfunction of Huntington's disease.

Abstract Background Preceding studies have reported the association of chronic neuropathic orofacial pain with altered ongoing function in the ventrolateral periaqueductal gray (vlPAG). However, its role in trigeminal neuralgia (TN) lacks attention. We here reported the aspect that vlPAG neurons play in TN nociceptive processing by employing excitatory neuron-specific optogenetic approaches. Methods TN was generated via unilateral infraorbital nerve chronic constriction in Sprague Dawley rats which induced mechanical and thermal pain sensitivity in air puff and acetone test, respectively. Channelrhodopsin conjugated virus with CamKIIα promoter was used to specifically activate the excitatory vlPAG neuronal population by optogenetic stimulation and in vivo microdialysis was done to determine its effect on the excitatory-inhibitory balance. In vivo extracellular recordings from ventral posteromedial (VPM) thalamus were assessed in response to vlPAG optogenetic stimulation. Depending on the experimental terms, unpaired student’s t test and two-way analysis of variance (ANOVA) were used for statistical analysis. Results We observed that optogenetic activation of vlPAG subgroup neurons markedly improved pain hypersensitivity in reflexive behavior tests which was also evident on microdialysis analysis with increase glutamate concentration during stimulation period. Decreased mean firing and burst rates were evident in VPM thalamic electrophysiological recordings during the stimulation period. Overall, our results suggest the optogenetic activation of vlPAG excitatory neurons in a TN rat model has pain ameliorating effect. Conclusions This article presents the prospect of pain modulation in trigeminal pain pathway via optogenetic activation of vlPAG excitatory neurons in rat model. This outlook could potentially assist vlPAG insight and its optogenetic approach in trigeminal neuropathic pain which aid clinicians endeavoring towards enhanced pain relief therapy in trigeminal neuralgia patients.

The trigeminal ganglion (TG) is the primary site of aberration in trigeminal neuralgia (TN), and hence a crucial site where afferent input can be modulated. Here, we postulated that inhibiting TG via optogenetics using flexible optic cannula would diminish brainstem trigeminal nucleus caudalis (TNC) neuronal activity and pain behavior in TN rat model. Infraorbital nerve constriction was employed to induce TN in female Sprague-Dawley rats, while naive and sham rats served as controls. TG-directed microinjections of AAV virus containing either the optogenetic or null vector were delivered to rats in each group. In vivo electrophysiological responses were obtained from the ventral posteromedial nucleus (VPm) of the thalamus with simultaneous TG optogenetic stimulation using flexible optic cannula as well the effects on behavioral responses were investigated. Recordings in TN rats revealed a decrease in burst firing activity during yellow laser driven inhibition on TG, as well as considerably improved behavioral responses. In contrast, we noticed persistent hypersensitivity and increased tonic firing with blue laser stimulation which indicates that TG inhibition can synchronize trigeminal pain signal transmission in a TN animal model. The potential of an optogenetic approach in TG itself with flexible optic fiber to directly disrupt the trigeminal pain circuitry delivers fundamental underpinnings toward its prospective as a trigeminal neuralgia management.

Newcastle disease (ND) is one of the major viral diseases of poultry, remains a constant threat in poultry farms that causes huge economic losses every year. However, little is known regarding the potential risk factors of the disease in broiler. The study was undertaken to ascertain the potential risk factors and biosecurity measures in ND prevalent broiler farm. A total of 116 broiler farms were considered as a sample size from a different area of Barishal district of Bangladesh in which 19.83% ND prevalence was found. In the findings, the farmers (33.62%) who had training on poultry farming, were significantly less ND positive case (7.69%). Besides this, among the different risk factors and biosecurity measures only shed location, ventilation, vaccination status, feeder and waterer cleaning frequency, visitors accession, pets in the farm, use of disinfectant and seasonal variation had significant effect on ND outbreak. However, among all the factors only farmers training (OR=0.025; 95% CI: 0.001-0.509), shed location (OR=0.035; 95% CI: 0.003-0.390), vaccination against ND (OR=0.017; 95% CI: 0.001-0.435) and use of disinfectant daily (OR=0.011; 95% CI: 0.000-0.294) made a unique statistically significant contribution to the regression model and the predictors had approximately similar strength on reporting ND outbreak. In completion, ND can be reduced in broiler farms by improving the level of common biosecurity, farm management practices, and minimizing the potential risk factors through training of farmers, awareness build-up, and enforcement of these practices on the farms.

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.

The nucleus accumbens core (NAcc) is an important component of brain reward circuitry, but studies have revealed its involvement in pain circuitry also. However, its effect on trigeminal neuralgia (TN) and the mechanism underlying it are yet to be fully understood. Therefore, this study aimed to examine the outcomes of optogenetic stimulation of NAcc GABAergic neurons in an animal model of TN. Animals were allocated into TN, sham, and control groups. TN was generated by infraorbital nerve constriction and the optogenetic virus was injected into the NAcc. In vivo extracellular recordings were acquired from the ventral posteromedial nucleus of the thalamus. Alterations of behavioral responses during stimulation “ON” and “OFF” conditions were evaluated. In vivo microdialysis was performed in the NAcc of TN and sham animals. During optogenetic stimulation, electrophysiological recordings revealed a reduction of both tonic and burst firing activity in TN animals, and significantly improved behavioral responses were observed as well. Microdialysis coupled with liquid chromatography/tandem mass spectrometry analysis revealed significant alterations in extracellular concentration levels of GABA, glutamate, acetylcholine, dopamine, and citrulline in NAcc upon optic stimulation. In fine, our results suggested that NAcc stimulation could modulate the transmission of trigeminal pain signals in the TN animal model.