Chemogenetic inhibition of trigeminal ganglion neurons attenuates behavioural and neural pain responses in a model of trigeminal neuropathic pain

Abstract

Background: Nerve injury can lead to ectopic activation of injured nociceptorsand central sensitization characterized by allodynia and hyperalgesia.Reduction in the activity of primary afferent neurons has been shown to be sufficient in alleviating peripherally generated pain. The cell bodies of such trigeminal nociceptors are located in the trigeminal ganglia (TG) with central processes that terminate in the brainstem trigeminal nucleus caudalis (TNC). The TG is therefore a strategic locus where afferent input can be manipulated. We hypothesized that chemogenetic inhibition of TG would suppress TNC neuronal activity and attenuate pain behaviour in a rat model of painful traumatic trigeminal neuropathy (PTTN).Methods: Trigeminal neuropathic pain was induced in adult male Sprague-Dawley rats (n = 24) via chronic constriction injury to the infraorbital nerve (ION-CCI). Naïve and sham rats were used as controls (n = 20/group). Rats within each group received TG-directed microinjections of AAV virus containing either the inhibitory hM4Di-DREADD construct or EGFP. Results: In the ION-CCI group, systemic administration of the DREADD agonist clozapine N-oxide (CNO) reversed the hypersensitivity phenotype in animals expressing hM4Di but not EGFP. CNO-mediated activation of hM4Di DREADD in ION-CCI animals was also associated with reduced Fos expression in the TNC elicited by repeated mechanical stimulation of the dermatome ipsilateral to the injury. There was no effect of CNO on pain behaviour or TNC Fos expression in eGFP animals. Conclusion:Our results indicate that DREADDs may offer an effective therapeutic approach for treatment of trigeminal neuropathic pain.Significance: Trigeminal neuropathic pain is highly resistant to therapy and we are in dire need of novel approaches. This study provides further evidence for the successful application of DREADDs as an effective tool for modulating central Olga A. Korczeniewska and Morgan H. James contributed equally to the research project and the manuscript.Gary Aston-Jones and Rafael Benoliel contributed equally to the research design and interpretation.

A novel implantable device for sensory and affective assessment of orofacial pain in rats

“…Consistent with previous report, ION-CCI rats exhibited hypersensitivity to both innoxious and noxious stimuli ( 6 , 36 ). A lower response threshold to electrical stimuli (4V) was found in ION-CCI rats compared with sham group, which did not display any evoked-behavior up to 10V stimulation ( Figures 3 , 6 ).…”

CaV3.2 calcium channels contribute to trigeminal neuralgia

“…21 The CION model has been widely used to study trigeminal neuropathic pain. 23,40,[44][45][46][47][48]55,61 In addition, the CION model, as well as other chronic trigeminal pain models, have been used to investigate underlying molecular mechanisms. 39,41,46,53,54 We reiterate that several chronic pain conditions, such as TN, migraine, and fibromyalgia, are more prevalent in women.…”

Spécificités de la douleur neuropathique oro-faciale

“…Cette cinétique d'activation suggère un rôle prépondérant des CSG lors des premières phases du développement de la neuropathie trigéminale post-traumatique [53]. Plus récemment, des auteurs ont montré qu'il était possible d'atténuer les symptômes douloureux provoqués par la lésion, en inhibant, par une approche chémogénétique (ou DREADD, pour designer receptor exclusively activated by designer drugs), les CSG du ganglion trigéminal [54].…”