Upregulation of TRPM3 in nociceptors innervating inflamed tissue

Abstract

Genetic ablation or pharmacological inhibition of the heat-activated cation channel TRPM3 alleviates inflammatory heat hyperalgesia, but the underlying mechanisms are unknown. We induced unilateral inflammation of the hind paw in mice, and directly compared expression and function of TRPM3 and two other heat-activated TRP channels (TRPV1 and TRPA1) in sensory neurons innervating the ipsilateral and contralateral paw. We detected increased Trpm3 mRNA levels in dorsal root ganglion neurons innervating the inflamed paw, and augmented TRP channel-mediated calcium responses, both in the cell bodies and the intact peripheral endings of nociceptors. In particular, inflammation provoked a pronounced increase in nociceptors with functional co-expression of TRPM3, TRPV1 and TRPA1. Finally, pharmacological inhibition of TRPM3 dampened TRPV1- and TRPA1-mediated responses in nociceptors innervating the inflamed paw, but not in those innervating healthy tissue. These insights into the mechanisms underlying inflammatory heat hypersensitivity provide a rationale for developing TRPM3 antagonists to treat pathological pain.

TRPM3 in Brain (Patho)Physiology

“…In good accordance with its thermosensitivity and expression by small-sized somatosensory neurons, TRPM3 plays a role in noxious heat sensation together with TRPV1 and TRPA1 (Vriens et al, 2011 ; Vandewauw et al, 2018 ; Vriens and Voets, 2018 , 2019 ). TRPM3 activation results in neuropeptide release from the sensory terminals (Held et al, 2015a ) and the channel is sensitized by inflammatory conditions, which may contribute to inflammatory hyperalgesia (Vriens et al, 2011 ; Mulier et al, 2020 ). In contrast to TRPV1, TRPM3 does not to appear to play a role in central thermoregulation and neither agonists nor antagonists induce noticeable changes in core body temperature (Vriens et al, 2011 ; Straub et al, 2013a ).…”

Optical Assessment of Nociceptive TRP Channel Function at the Peripheral Nerve Terminal

“…Imaging of nociceptive terminal activity in paw skin in vivo or ex vivo requires confocal or multiphoton microscopy with long (seconds) frame acquisition times. Recently, Ca 2+ signals from terminal branches of skin nociceptive neurons ex vivo were analyzed using a spinning disk confocal microscope at a 0.25 Hz acquisition rate [ 27 ]. The authors recorded the activity of nociceptive terminal branches in a skin-nerve preparation consisting of a skin flap from the hind paw’s dorsal surface and the innervating saphenous nerve from mice expressing GCaMP3 in TRPV1-expressing neurons.…”

“…Due to the low drug permeability of the epidermis, the skin flap was placed with the dermis side up, and TRP channel agonists were applied from above, thus the imaging of the terminals was performed from the epidermal side using an inverted confocal microscope. Imaging of the skin nociceptive terminal branches while applying various activators of TRP channels revealed increased activity of TRPM3 channels during complete Freund’s adjuvant (CFA)-mediated skin inflammation, emphasizing the role of terminals’ TRPM3 channels in inflammatory pain [ 27 ].…”

“…While these experimental approaches provide a high temporal resolution on peripheral nerve activity, they do not allow for enough spatial resolution regarding where at the nerve terminal this activity occurs. In this respect, the recent development of optical recording techniques is a big step in overcoming these significant technical limitations [ 25 , 26 , 27 , 28 , 29 , 30 ].…”

Novel Analgesics with Peripheral Targets

“…TRPM3 activation evokes pain-related behavior in animals [209], and the contribution to heat pain in mice as part of a triad of redundancy in heat perception render this interesting [210]. In addition, TRPM3 is upregulated in inflammatory conditions, which increases the overlap with and the interaction with signaling of TRPV1 and TRPA1 [211]. TRPM3 is found in human sensory neurons [212], and concentrations of volatile anesthetics not exceeding the minimal alveolar concentration by far can act as TRPM3 antagonists [213].…”