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.

Several ion channels and transporters regulate fluid secretion in salivary and lacrimal glands. In salivary glands, the major anion channel involved in fluid secretion is the calcium‐activated chloride channel anoctamin 1 (ANO1). Several members of the transient receptor potential (TRP) channel superfamily regulate ANO1 activity. Here, we report a functional interaction between thermosensitive TRP vanilloid (TRPV)4 and ANO1 in acinar cells isolated from mouse salivary and lacrimal glands. TRPV4 activation induced chloride currents and shrinkage of acinar cells by increasing intracellular calcium concentrations. The chloride currents evoked by a TRPV4‐specific activator (GSK1016790A) were identified as ANOl‐mediated currents. Moreover, TRPV4 activation by an inositol 1,4,5‐trisphosphate (IP ₃ )‐dependent mechanism was found to contribute to the muscarinic pathway of fluid secretion. Muscarinic stimulation of saliva and tear secretion was down‐regulated in both TRPV4‐deficient mice and in acinar cells treated with a TRPV4‐specific antagonist (HC‐067047). Furthermore, the temperature dependence of muscarinic salivation was shown to depend mainly on TRPV4. Our results suggest that TRPV4 interacts with IP ₃ receptors and ANO1 to regulate the muscarinic pathway that mediates salivation and lacrimation.— Derouiche, S., Takayama, Y., Murakami, M., Tominaga, M. TRPV4 heats up ANO1‐dependent exocrine gland fluid secretion. FASEB J. 32, 1841–1854 (2018). www.fasebj.org

Arthropods are the largest group of living organisms and among them, mosquitoes spread parasites and viruses causing deathly diseases. They can spread easily these pathogens because of their painless skin piercing. Although the lack of pain is mainly due to the thinness of their fascicle, it is possible that mosquito saliva, which is discharged during their piercing, might contribute. If mosquito saliva contains antinociceptive substances, it should act on the sensory neurons innervating the epidermis where there are several ion channels that can detect noxious stimuli such as the transient receptor potential (TRP) channels. We found that mosquito head homogenates and mouse saliva inhibit TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) channels, either heterologously expressed in HEK293T cells or endogenously expressed in native mouse sensory neurons. Among the different substances contained in mosquito head homogenates or mouse saliva, we have also identified sialorphin as a candidate antinociceptive peptide as it showed similar inhibition effects on TRPV1 and TRPA1. Finally, we confirmed the antinociceptive effects of mosquito head homogenates, mouse saliva and sialorphin in vivo by observing decreased pain-related behaviors in mice co-injected with these substances. Similar inhibitory effects of mosquito head homogenates and mouse saliva on TRPV1 and TRPA1 suggest that the antinociceptive effects of saliva are universal, which could explain why many animals including humans often lick their wounds. These findings would lead to the development of novel and safe antinociceptive agents.

Summary: Whooping cough, a contagious respiratory disease caused by Bordetella pertussis , is characterized by paroxysmal coughing; however, the mechanism has not been studied because of the lack of versatile animal models that reproduce the cough. Here, we present a mouse model that reproduces coughing after intranasal inoculation with the bacteria or its components and demonstrate that lipooligosaccharide (LOS), pertussis toxin (PTx), and Vag8 of the bacteria cooperatively function to cause coughing. LOS-induced bradykinin sensitized a transient receptor potential ion channel, TRPV1, which acts as a sensor to evoke the cough reflex. Vag8 further increased bradykinin levels by inhibiting the C1 esterase inhibitor, the major downregulator of the contact system, which generates bradykinin. PTx inhibits intrinsic negative regulation systems for TRPV1 through inactivation of G _i GTPases. Our findings provide a basis for answering long-standing questions on the pathophysiology of the pertussis cough.

Arthropods are the largest group of living organisms and among them, mosquitoes spread parasites and viruses causing deathly diseases. Mosquito’s painless piercing is due to the thinness of their fascicle, but mosquito saliva might also contribute to it. We found that mosquito and mouse saliva inhibit TRPV1 and TRPA1 channels, either heterologously expressed in HEK293T cells or endogenously expressed in native mouse sensory neurons. We have also identified sialorphin as a candidate antinociceptive peptide as it showed similar effects on TRPV1 and TRPA1. Finally, we confirmed the antinociceptive effects of saliva and sialorphin in vivo by observing decreased pain-related behaviors in mice coinjected with these substances. Similar inhibitory effects of mosquito and mouse saliva suggest that the antinociceptive effects of saliva are universal, which could explain why many animals including humans often lick their wounds. These findings would lead to the development of novel anti-nociceptive agents.