Primidone inhibits TRPM3 and attenuates thermal nociception in vivo

Abstract

Supplemental Digital Content is Available in the Text.The approved antiepileptic drug primidone potently inhibits TRPM3 channels and thereby exerts analgesic properties to chemical pain and thermal hyperalgesia in mice.

Disease-associated mutations in TRPM3 render the channel overactive via two distinct mechanisms

“…Given the increased constitutive activity of the mutants at body temperature, increased neuronal excitability and/or Ca 2+ -induced neuronal damage is a possible disease-causing mechanism. Primidone is a clinically approved antiepileptic drug; it is thought to exert its effects by being converted to barbiturate by the liver, but it crosses the blood brain barrier (Nagaki et al, 1999), and directly inhibits TRPM3 activity even below its therapeutic concentration (Krugel et al, 2017). Our data showing that primidone inhibited the basal activity of the mutant channels, suggests a potential therapy for this newly described channelopathy.…”

“…Both mutants showed constitutive activity that was inhibited by the TRPM3 antagonist primidone. As primidone is a clinically used medication (Krugel et al, 2017), our findings offer potential clinical intervention to treat this channelopathy. We also find that the Val to Met substitution in the S4-S5 loop induced a larger left shift in the concentration response relationship to PregS and CIM0216 than the Pro to Gln substitution close to the pore-loop in the extracellular segment of S6.…”

“…TRPM3 is a well-established temperature sensor in peripheral sensory neurons of the dorsal root ganglia (DRG); its genetic deletion in mice leads to defects in noxious heat sensation as well as reduced inflammatory heat hyperalgesia (Vriens et al, 2011;Vandewauw et al, 2018). Inhibitors of TRPM3 also reduced both acute heat sensation and inflammatory heat hyperalgesia (Straub et al, 2013;Krugel et al, 2017). While TRPM3 -/mice show defects in noxious heat sensation, the channel shows increased activity well below the noxious range, when temperature is increased from 15 o C to 26 o C, with further increases in activity at 37 o C (Vriens et al, 2011).…”

Antinociceptive Effects of Isosakuranetin in a Rat Model of Peripheral Neuropathy

“…As stated above, the natural-occurring TRPM3 blocker isosakuranetin is able to reduce acute heat nociception and inflammatory hyperalgesia [10]. Primidone and diclofenac have been shown to be TRPM3 blockers and are found to be effective in thermal and inflammatory pain [21,22]. It is of importance that recently a synthetic compound CIM0216 has been characterized as a TRPM3 activator, and the application of CIM0216 elicited the release of the peptides calcitonin gene-related peptide from sensory nerve terminals and induces a TRPM3-dependent nocifensive behavior [23], supporting the important role of TRPM3 in pain processing.…”

Heat sensing involves a TRiPlet of ion channels

“…Similarly, a prolonged latency in heat sensitivity was observed in mice after systemic treatment with inhibitors of TRPM3 (Krugel, Straub, Beckmann, & Schaefer, 2017;Straub et al, 2013). However, a substantial fraction of heat-responsive cells was still observed after treatment of Trpm3 −/− neurons with a specific TRPV1 antagonist (Vriens et al, 2011), indicating the existence of one or more additional heat sensor in sensory neurons.…”