Antagonism of Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Trigeminal Neuropathic Pain: Study in an Animal Model.

Chiara Demartini,Kristof Deseure,Oscar Francesconi,Cristina Nativi,Rosaria Greco,Cristina Tassorelli,Anna Zanaboni

doi:10.3390/ijms19113320

Abstract

Transient receptor potential ankyrin type-1 (TRPA1) channels are known to actively participate in different pain conditions, including trigeminal neuropathic pain, whose clinical treatment is still unsatisfactory. The aim of this study was to evaluate the involvement of TRPA1 channels by means of the antagonist ADM_12 in trigeminal neuropathic pain, in order to identify possible therapeutic targets. A single treatment of ADM_12 in rats 4 weeks after the chronic constriction injury of the infraorbital nerve (IoN-CCI) significantly reduced the mechanical allodynia induced in the IoN-CCI rats. Additionally, ADM_12 was able to abolish the increased levels of TRPA1, calcitonin gene-related peptide (CGRP), substance P (SP), and cytokines gene expression in trigeminal ganglia, cervical spinal cord, and medulla induced in the IoN-CCI rats. By contrast, no significant differences between groups were seen as regards CGRP and SP protein expression in the pars caudalis of the spinal nucleus of the trigeminal nerve. ADM_12 also reduced TRP vanilloid type-1 (TRPV1) gene expression in the same areas after IoN-CCI. Our findings show the involvement of both TRPA1 and TRPV1 channels in trigeminal neuropathic pain, and in particular, in trigeminal mechanical allodynia. Furthermore, they provide grounds for the use of ADM_12 in the treatment of trigeminal neuropathic pain.

Highlights

Trigeminal neuralgia (TN) is a rare condition characterized by paroxysmal attacks of sharp pain, frequently described as an “electric shock”
In agreement with Deseure and Hans [18], 5 days after surgery, the two groups of rats that underwent infraorbital nerve (IoN)-CCI displayed a lack of responsiveness to ipsilateral mechanical stimulation testing (MST) of the IoN territory (Figure 1A)
On day +27, the administration of the TRPA1 antagonist treatment in operated rats (IoN-CCI2 group) reduced the response score of the mechanical stimulation compared to the IoN-CCI1 group (Figure 1B); whereas, ADM_12 treatment in sham-operated rats (Sham2 group) did not change the mechanical response

Summary

Introduction

Trigeminal neuralgia (TN) is a rare condition characterized by paroxysmal attacks of sharp pain, frequently described as an “electric shock”. Up to 50% of patients with trigeminal neuralgia have continuous pain in the same territory, which results in greater diagnostic difficulties, higher disability, and lower response to medical and surgical treatments [1]. Three diagnostic categories of TN are identified by the recent classification of headache disorders: Classical (without apparent cause other than neurovascular compression), secondary (caused by an underlying neurological disorder), and idiopathic (no cause is found) [2]. Medications for TN exist, but they are poorly tolerated or ineffective. For this reason, multiple surgical approaches have been developed, but a portion of patients are refractory to both medical and surgical approaches [4,5]. There is need for further investigation into the mechanisms underlying pain in TN in order to identify new, possibly more effective, therapeutic targets

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