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Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity.

ABSTRACT: Cranial allodynia associated with spontaneous migraine is reported as either responsive to triptan treatment or to be predictive of lack of triptan efficacy. These conflicting results suggest that a single mechanism mediating the underlying neurophysiology of migraine symptoms is unlikely. The lack of a translational approach to study cranial allodynia reported in migraine patients is a limitation in dissecting potential mechanisms. Our objective was to study triptan-responsive cranial allodynia in migraine patients, and to develop an approach to studying its neural basis in the laboratory. Using nitroglycerine to trigger migraine attacks, we investigated whether cranial allodynia could be triggered experimentally, observing its response to treatment. Preclinically, we examined the cephalic response properties of central trigeminocervical neurons using extracellular recording techniques, determining changes to ongoing firing and somatosensory cranial-evoked sensitivity, in response to nitroglycerine followed by triptan treatment. Cranial allodynia was triggered alongside migraine-like headache in nearly half of subjects. Those who reported cranial allodynia accompanying their spontaneous migraine attacks were significantly more likely to have symptoms triggered than those that did not. Patients responded to treatment with aspirin or sumatriptan. Preclinically, nitroglycerine caused an increase in ongoing firing and hypersensitivity to intracranial-dural and extracranial-cutaneous (noxious and innocuous) somatosensory stimulation, reflecting signatures of central sensitization potentially mediating throbbing headache and cranial allodynia. These responses were aborted by a triptan. These data suggest that nitroglycerine can be used as an effective and reliable method to trigger cranial allodynia in subjects during evoked migraine, and the symptom is responsive to abortive triptan treatments. Preclinically, nitroglycerine activates the underlying neural mechanism of cephalic migraine symptoms, central sensitization, also predicting the clinical outcome to triptans. This supports a biological rationale that several mechanisms can mediate the underlying neurophysiology of migraine symptoms, with nitrergic-induced changes reflecting one that is relevant to spontaneous migraine in many migraineurs, whose symptoms of cranial allodynia are responsive to triptan treatment. This approach translates directly to responses in animals and is therefore a relevant platform to study migraine pathophysiology, and for use in migraine drug discovery.

SUBMITTER: Akerman S

PROVIDER: S-EPMC6308314 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Objective Previous studies of neuropathic pain have suggested that the P2X4 purinoceptor (P2X4R) in spinal microglia is essential for maintaining allodynia following nerve injury. However, little is known about its role in inflammatory soup-induced trigeminal allodynia, which closely mimics chronic migraine status. Here, we determined the contributions of P2X4R and related signaling pathways in an inflammatory soup-induced trigeminal allodynia model. Methods P2X4R gene and protein levels in the trigeminal nucleus caudalis were analyzed following repeated dural inflammatory soup infusions. p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels in the trigeminal nucleus caudalis, as well as trigeminal sensitivity, were assessed among the different groups. Immunofluorescence staining was used to detect protein localization and expression in the trigeminal nucleus caudalis. Results Repeated inflammatory dural stimulation induced trigeminal hyperalgesia and the upregulation of P2X4R. Immunofluorescence revealed that P2X4R was expressed in trigeminal nucleus caudalis microglial cells. Blockage of P2X4R produced an anti-nociceptive effect, which was associated with an inhibition of inflammatory soup-induced increases in p38, brain-derived neurotrophic factor, excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide protein levels. The tyrosine receptor kinase B antagonist ANA-12 reversed trigeminal allodynia and the upregulation of excitatory amino acid transporter 3, c-Fos, and calcitonin gene-related peptide, whereas the agonist 7,8-dihydroxyflavone exacerbated these effects. Double immunostaining indicated that p38 and brain-derived neurotrophic factor were mainly expressed in microglial cells, whereas excitatory amino acid transporter 3 was primarily expressed in trigeminal nucleus caudalis neurons. Conclusions These data indicate that microglial P2X4R is involved in the regulation of excitatory amino acid transporter 3 via brain-derived neurotrophic factor-tyrosine receptor kinase B signaling following repeated inflammatory dural stimulation. Microglial P2X4R activation and microglia-neuron interactions in the trigeminal nucleus caudalis may play a role in the pathogenesis of migraine chronicity, and the modulation of P2X4R activation might be a potential therapeutic strategy.

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.

Project description:Trigeminal neuralgia (TN) is debilitating and is usually accompanied by mood disorders. The lateral habenula (LHb) is considered to be involved in the modulation of pain and mood disorders, and the present study aimed to determine if and how the LHb participates in the development of pain and anxiety in TN. To address this issue, a mouse model of partial transection of the infraorbital nerve (pT-ION) was established. pT-ION induced stable and long-lasting primary and secondary orofacial allodynia and anxiety-like behaviors that correlated with the increased excitability of LHb neurons. Adeno-associated virus (AAV)-mediated expression of hM4D(Gi) in glutamatergic neurons of the unilateral LHb followed by clozapine-N-oxide application relieved pT-ION-induced anxiety-like behaviors but not allodynia. Immunofluorescence validated the successful infection of AAV in the LHb, and microarray analysis showed changes in gene expression in the LHb of mice showing allodynia and anxiety-like behaviors after pT-ION. Among these differentially expressed genes was Tacr3, the downregulation of which was validated by RT-qPCR. Rescuing the downregulation of Tacr3 by AAV-mediated Tacr3 overexpression in the unilateral LHb significantly reversed pT-ION-induced anxiety-like behaviors but not allodynia. Whole-cell patch clamp recording showed that Tacr3 overexpression suppressed nerve injury-induced hyperexcitation of LHb neurons, and western blotting showed that the pT-ION-induced upregulation of p-CaMKII was reversed by AAV-mediated Tacr3 overexpression or chemicogenetic inhibition of glutamatergic neurons in the LHb. Moreover, not only anxiety-like behaviors, but also allodynia after pT-ION were significantly alleviated by chemicogenetic inhibition of bilateral LHb neurons or by bilateral Tacr3 overexpression in the LHb. In conclusion, Tacr3 in the LHb plays a protective role in treating trigeminal nerve injury-induced allodynia and anxiety-like behaviors by suppressing the hyperexcitability of LHb neurons. These findings provide a rationale for suppressing unilateral or bilateral LHb activity by targeting Tacr3 in treating the anxiety and pain associated with TN.

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Nitroglycerine triggers triptan-responsive cranial allodynia and trigeminal neuronal hypersensitivity.

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