Characterization of peripheral nociceptors during chronic secondary painexperimental studies in mice

Abstract

Chronic Pain is one main cause of human suffering and disability, affecting 20% of the global population. However, we still lack effective treatment. Among the different forms of chronic pain, orofacial and neuropathic pain are of special interest in our research groups. As orofacial pain is concerned, dental pain is unique, because stimulation of teeth only produces pain as feeling, with cold as the most prominent stimuli to evoke this sensation. There are several ion channels of the transient receptor potential (TRP) family (mainly TRPM8, TRPA1) that, at least in cutaneous nociceptors with their cell bodies in the dorsal root ganglia, participate in cold transduction. However, fewer studies have involved primary afferents innervating the teeth, in which cell bodies are located in the trigeminal ganglia together with cell bodies of neurons innervating other facial organs and structures. We optimized a method to specifically study primary afferent nociceptors innervating the tooth pulp of the mouse by retrograde labelling and found expression of different TRP channels in dental primary afferent neurons. Its combination with other methodologies will be the basis for futures studies on dental chronic pain and cold transduction mechanisms. Within the entity of neuropathic pain, spontaneous pain is the main symptom reported by patients, which has been linked to spontaneous discharges in peripheral nociceptors. However, as most of the previous studies have focused on the evaluation of stimulus-induced symptoms, the underlying causes of spontaneous activity remain unclear. We used a mouse model of partial damage of a peripheral nerve and showed a high incidence of spontaneous nociceptors firing action potentials at constant rates. Using pharmacological tools, we demonstrated the contribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and a member of the voltage-gated potassium channel subfamily KQT (Kv7) to ectopic spontaneous activity in peripheral nociceptors. Our results suggest HCN and Kv7 channels as peripheral targets to treat neuropathic pain.