Suppression of Pain in the Late Phase of Chronic Trigeminal Neuropathic Pain Failed to Rescue the Decision-Making Deficits in Rats.
Ontology highlight
ABSTRACT:
SUBMITTER: Murugappan SK
PROVIDER: S-EPMC8346079 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The aim of this study was to investigate whether astroglia in the medullary dorsal horn (trigeminal spinal subnucleus caudalis; Vc) may be involved in orofacial neuropathic pain following trigeminal nerve injury. The effects of intrathecal administration of the astroglial aconitase inhibitor sodium fluoroacetate (FA) were tested on Vc astroglial hyperactivity [as revealed by glial fibrillary acid protein (GFAP) labeling], nocifensive behavior, Vc extracellular signal-regulated kinase phosphorylation (pERK), and Vc neuronal activity in inferior alveolar nerve-transected (IANX) rats. Compared with sham-control rats, a significant increase occurred in GFAP-positive cells in ipsilateral Vc at postoperative day 7 in IANX rats, which was prevented following FA administration. FA significantly increased the reduced head withdrawal latency to high-intensity heat stimulation of the maxillary whisker pad skin in IANX rats, although it did not significantly affect the reduced escape threshold to low-intensity mechanical stimulation of the whisker skin in IANX rats. FA also significantly reduced the increased number of pERK-like immunoreactive cells in Vc and the enhanced Vc nociceptive neuronal responses following high-intensity skin stimulation that were documented in IANX rats, and glutamine administration restored the enhanced responses. These various findings provide the first documentation that astroglia is involved in the enhanced nociceptive responses of functionally identified Vc nociceptive neurons and in the associated orofacial hyperalgesia following trigeminal nerve injury.
| S-EPMC2804401 | biostudies-literature
Project description:Using a rat model of trigeminal neuropathic pain (TNP) produced by chronic compression of the infraorbital nerve (CCI-ION), we investigated the analgesic effect and the underlying mechanisms of ceftriaxone (Cef), a ?-lactam antibiotic, that is thought to be a potent stimulator of glutamate transporter 1 (GLT-1). First, repeated intraperitoneal (i.p.) injections of Cef (200 mg/kg) for 5-days since Day 1 of CCI-ION could significantly relieve both mechanical and thermal pain hypersensitivity from day 10 after drug administration. Western blot and immunofluorescent results demonstrated that 5-days administration of Cef resulted in the restoration of GLT-1 expression to a level equivalent to the sham control which was dramatically lost under the TNP condition. Moreover, multi-electrode (8 × 8) array recordings of network field excitatory postsynaptic potentials (fEPSPs) were performed on the acutely dissociated medullary dorsal horn slice evoked by electrical stimulation of the trigeminal spinal tract. The results showed that the increased number of fEPSPs, induction rate, and maintenance of long-term potentiation caused by CCI-ION were significantly suppressed by 5-days administration of Cef. Taken together, the results indicate that Cef can relieve TNP through suppression of spatiotemporal synaptic plasticity via GLT-1 restoration in the medullary dorsal horn of the trigeminal nerve.
| S-EPMC7340123 | biostudies-literature
Project description: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 Ca(2+) 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.
| S-EPMC4776481 | biostudies-other
Project description:Neuropathic pain in pediatric oncology can be caused by distinct lesions or disease processes affecting the somatosensory system, including chemotherapy-related neuronal injury, solid tumor-related involvement of neural structures, post-surgical neuropathic pain-including phantom limb pain and pain after limb-sparing surgery-and the complex circumstances of neuropathic pain at the end of life. Treatment algorithms reflect the general treatment principles applied for adult neuropathic pain, but the dose regimens applied in children are modest and rarely escalated to the maximum doses to optimize analgesic efficacy. Pharmacological management of neuropathic pain should be based on a stepwise intervention strategy, as combinations of medications are the most effective approach. Gabapentinoids and tricyclic antidepressants are recommended as first-line therapy. Methadone, ketamine, and lidocaine may be useful adjuvants in selected patients. Prospective studies extended over a substantial length of time are recommended because of the nature of neuropathic pain as persistent, chronic pain and based on the need for sufficient time to escalate medication dose regimens to full analgesic efficacy.
| S-EPMC6779139 | biostudies-literature
Project description:Hyperdopaminergic states in mental disorders are associated with disruptive deficits in decision making. However, the precise contribution of topographically distinct mesencephalic dopamine pathways to decision-making processes remains elusive. Here we show, using a multidisciplinary approach, how hyperactivity of ascending projections from the ventral tegmental area (VTA) contributes to impaired flexible decision making in rats. Activation of the VTA-nucleus accumbens pathway leads to insensitivity to loss and punishment due to impaired processing of negative reward prediction errors. In contrast, activation of the VTA-prefrontal cortex pathway promotes risky decision making without affecting the ability to choose the economically most beneficial option. Together, these findings show how malfunction of ascending VTA projections affects value-based decision making, suggesting a potential mechanism through which increased forebrain dopamine signaling leads to aberrant behavior, as is seen in substance abuse, mania, and after dopamine replacement therapy in Parkinson's disease.
| S-EPMC5821846 | biostudies-other
Project description:BackgroundRecent data suggests that in chronic pain there are changes in gray matter consistent with decreased brain volume, indicating that the disease process may produce morphological changes in the brains of those affected. However, no study has evaluated cortical thickness in relation to specific functional changes in evoked pain. In this study we sought to investigate structural (gray matter thickness) and functional (blood oxygenation dependent level - BOLD) changes in cortical regions of precisely matched patients with chronic trigeminal neuropathic pain (TNP) affecting the right maxillary (V2) division of the trigeminal nerve. The model has a number of advantages including the evaluation of specific changes that can be mapped to known somatotopic anatomy.Methodology/principal findingsCortical regions were chosen based on sensory (Somatosensory cortex (SI and SII), motor (MI) and posterior insula), or emotional (DLPFC, Frontal, Anterior Insula, Cingulate) processing of pain. Both structural and functional (to brush-induced allodynia) scans were obtained and averaged from two different imaging sessions separated by 2-6 months in all patients. Age and gender-matched healthy controls were also scanned twice for cortical thickness measurement. Changes in cortical thickness of TNP patients were frequently colocalized and correlated with functional allodynic activations, and included both cortical thickening and thinning in sensorimotor regions, and predominantly thinning in emotional regions.ConclusionsOverall, such patterns of cortical thickness suggest a dynamic functionally-driven plasticity of the brain. These structural changes, which correlated with the pain duration, age-at-onset, pain intensity and cortical activity, may be specific targets for evaluating therapeutic interventions.
| S-EPMC2561059 | biostudies-literature
Project description:To investigate a potential mechanism underlying trigeminal nerve injury-induced orofacial hypersensitivity, we used a rat model of chronic constriction injury to the infraorbital nerve (CCI-ION) to study whether CCI-ION caused calcium channel α2δ1 (Cavα2δ1) protein dysregulation in trigeminal ganglia and associated spinal subnucleus caudalis and C1/C2 cervical dorsal spinal cord (Vc/C2). Furthermore, we studied whether this neuroplasticity contributed to spinal neuron sensitization and neuropathic pain states. CCI-ION caused orofacial hypersensitivity that correlated with Cavα2δ1 up-regulation in trigeminal ganglion neurons and Vc/C2. Blocking Cavα2δ1 with gabapentin, a ligand for the Cavα2δ1 proteins, or Cavα2δ1 antisense oligodeoxynucleotides led to a reversal of orofacial hypersensitivity, supporting an important role of Cavα2δ1 in orofacial pain processing. Importantly, increased Cavα2δ1 in Vc/C2 superficial dorsal horn was associated with increased excitatory synaptogenesis and increased frequency, but not the amplitude, of miniature excitatory postsynaptic currents in dorsal horn neurons that could be blocked by gabapentin. Thus, CCI-ION-induced Cavα2δ1 up-regulation may contribute to orofacial neuropathic pain states through abnormal excitatory synapse formation and enhanced presynaptic excitatory neurotransmitter release in Vc/C2.
| S-EPMC3945363 | biostudies-literature
Project description:Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy, and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca2+-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the preexisting pathologic pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain are controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage (TRPV1-LN) afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal in vivo two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of TNP.
| S-EPMC7266139 | biostudies-literature
Project description:Trigeminal neuropathic pain is the most debilitating pain disorder but current treatments including opiates are not effective. A common symptom of trigeminal neuropathic pain is cold allodynia/hyperalgesia or cold hypersensitivity in orofacial area, a region where exposure to cooling temperatures are inevitable in daily life. Mechanisms underlying trigeminal neuropathic pain manifested with cold hypersensitivity are not fully understood. In this study, we investigated trigeminal neuropathic pain in male rats following infraorbital nerve chronic constrictive injury (ION-CCI). Assessed by the orofacial operant behavioral test, ION-CCI animals displayed orofacial cold hypersensitivity. The cold hypersensitivity was associated with the hyperexcitability of small-sized trigeminal ganglion (TG) neurons that innervated orofacial regions. Furthermore, ION-CCI resulted in a reduction of A-type voltage-gated K+ currents (IA currents) in these TG neurons. We further showed that these small-sized TG neurons expressed Kv4.3 voltage-gated K+ channels, and Kv4.3 expression in these cells was significantly downregulated following ION-CCI. Pharmacological inhibition of Kv4.3 channels with phrixotoxin-2 inhibited IA-currents in these TG neurons and induced orofacial cold hypersensitivity. On the other hand, pharmacological potentiation of Kv4.3 channels amplified IA currents in these TG neurons and alleviated orofacial cold hypersensitivity in ION-CCI rats. Collectively, Kv4.3 downregulation in nociceptive trigeminal afferent fibers may contribute to peripheral cold hypersensitivity following trigeminal nerve injury, and Kv4.3 activators may be clinically useful to alleviate trigeminal neuropathic pain.SIGNIFICANCE STATEMENT Trigeminal neuropathic pain, the most debilitating pain disorder, is often triggered and exacerbated by cooling temperatures. Here, we created infraorbital nerve chronic constrictive injury (ION-CCI) in rats, an animal model of trigeminal neuropathic pain to show that dysfunction of Kv4.3 voltage-gated K+ channels in nociceptive-like trigeminal ganglion (TG) neurons underlies the trigeminal neuropathic pain manifested with cold hypersensitivity in orofacial regions. Furthermore, we demonstrate that pharmacological potentiation of Kv4.3 channels can alleviate orofacial cold hypersensitivity in ION-CCI rats. Our results may have clinical implications in trigeminal neuropathic pain in human patients, and Kv4.3 channels may be an effective therapeutic target for this devastating pain disorder.
| S-EPMC8018767 | biostudies-literature
Project description:BackgroundTrigeminal neuralgia is a characteristic disease that manifests as orofacial phasic or continuous severe pain triggered by innocuous orofacial stimulation; its mechanisms are not fully understood. In this study, we established a new animal model of trigeminal neuralgia and investigated the role of P2X3 receptor (P2X3R) alteration in the trigeminal ganglion (TG) via tumor necrosis factor alpha (TNFα) signaling in persistent orofacial pain.MethodsTrigeminal nerve root compression (TNC) was performed in male Sprague-Dawley rats. Changes in the mechanical sensitivity of whisker pad skin, amount of TNFα in the TG, and number of P2X3R and TNF receptor-2 (TNFR2)-positive TG neurons were assessed following TNC. The effects of TNFR2 antagonism in TG and subcutaneous P2X3R antagonism on mechanical hypersensitivity following TNC were examined.ResultsTNC induced unilateral continuous orofacial mechanical allodynia, which was depressed by carbamazepine. The accumulation of macrophages showing amoeboid-like morphological changes and expression of TNFα in the TG was remarkably increased following TNC treatment. The number of P2X3R- and TNFR2-positive TG neurons innervating the orofacial skin was significantly increased following TNC. TNFα was released from activated macrophages that occurred in the TG following TNC, and TNFR2 antagonism in the TG significantly diminished the TNC-induced increase in P2X3R-immunoreactive TG neurons. Moreover, subcutaneous P2X3R antagonism in the whisker pad skin significantly depressed TNC-induced mechanical allodynia.ConclusionsTherefore, it can be concluded that the signaling of TNFα released from activated macrophages in the TG induces the upregulation of P2X3R expression in TG neurons innervating the orofacial region, resulting in orofacial mechanical allodynia following TNC.
| S-EPMC8077728 | biostudies-literature