Emerging Perspectives on Pain Management by Modulation of TRP Channels and ANO1

Abstract

Receptor-type ion channels are critical for detection of noxious stimuli in primary sensory neurons. Transient receptor potential (TRP) channels mediate pain sensations and promote a variety of neuronal signals that elicit secondary neural functions (such as calcitonin gene-related peptide [CGRP] secretion), which are important for physiological functions throughout the body. In this review, we focus on the involvement of TRP channels in sensing acute pain, inflammatory pain, headache, migraine, pain due to fungal infections, and osteo-inflammation. Furthermore, action potentials mediated via interactions between TRP channels and the chloride channel, anoctamin 1 (ANO1), can also generate strong pain sensations in primary sensory neurons. Thus, we also discuss mechanisms that enhance neuronal excitation and are dependent on ANO1, and consider modulation of pain sensation from the perspective of both cation and anion dynamics.

Keywords: ANO1; Candidiasis; TRPA1; TRPM3; TRPV1; acute pain; inflammatory pain; migraine.

Figure 1

Nociceptor populations in substantia gelatinosa (SG) neurons of lamina II, which receive nociceptive inputs from dorsal root ganglion (DRG) neurons, no neurons respond only to TRPA1-associated stimuli. Approximately 30% of SG neurons are double-positive to capsaicin (CAP) and cinnamaldehyde (CA), 45% of SG neurons response to only CAP, and 25% of neurons show no effect to either CAP or CA. There are calcitonin gene-related peptide (CGRP)-positive and -negative neurons in peripheral sensory nerves. Most TRPV1–TMEM100–TRPA1 complexes and TRPV1–TRPA1–TRPM3 trios are expressed in CGRP-positive neurons. Anoctamin 1 (ANO1) is also expressed in CGRP-positive neurons, however approximately 70% of ANO1-expressing neurons are CGRP-negative.

Figure 2

Transient receptor potential (TRP) channels in the trigeminovascular system and migraine development. Migraine triggering events remain unknown and may be a central or peripheral process. The precise order of events contributing to migraine pain is also debated. It is generally admitted that activation and sensitization of primary afferent nociceptors that innervate the dural and meningeal vasculature trigger both calcitonin gene-related peptide (CGRP)-induced vasodilatation and neurogenic inflammation. Pain signals pass through the trigeminal nucleus caudalis, which relays signals to higher order neurons in the thalamus and cortex (green arrows). A trigemino–parasympathetic or trigeminal autonomic reflex arc passes through the sphenopalatine ganglion and is responsible for migraine pain by mediating neurogenic inflammation (blue arrow). Central and peripheral sensitization (pink arrows) may contribute to maintenance of pain signals and predispose to future migraine attacks. Transient receptor potential (TRP) vanilloid 1 (TRPV1) and anoctamin 1 (ANO1) might be involved in initiation, nociception, and sensitization processes of migraine. TRP ankyrin 1 (TRPA1) might be more relevant in the initiation phase. There are few studies available on TRPV4 and TRP melastatin 8 (TRPM8), yet these receptors might be important in pain signal transmission or neurogenic inflammation.

Figure 3

Bone protection system from Candida infection. Bone disruption followed by inflammation is worsened by overactive osteoclasts. Nociceptors suppress osteoclast development through calcitonin gene-related peptide (CGRP) release. The process involves: (1) Candida albicans is activated in an optimal environment (e.g., body temperature); (2) β-glucan released from pseudohyphae bind to its receptor, dectin-1, on the plasma membrane of keratinocytes; (3) ATP release from keratinocytes is enhanced through the phospholipase C (PLC) pathway; (4) neuronal excitation in voltage-gated sodium channel 1.8 (Nav1.8)-positive dorsal root ganglion (DRG) neurons; and (5) CGRP release from DRG neurons. Jun dimerization protein 2 (Jdp2) is activated by CGRP through a cAMP cascade in myeloid cells. In turn, tumor necrosis factor-alpha (TNF-α release (which accelerates osteoclast development) is suppressed. TNF-α-dependent inflammation is induced by the direct effect of β-glucan on myeloid cells. Furthermore, the CGRP–cAMP axis in osteoclasts also inhibits over-development. Thus, these pathways from skin to bone induce bone protection and inhibit bone inflammation during fungus infection.