The terpenes camphene and alpha-bisabolol inhibit inflammatory and neuropathic pain via Cav3.2 T-type calcium channels

Abstract

T-type calcium channels are known molecular targets of certain phytocannabinoids and endocannabinoids. Here we explored the modulation of Cav3.2 T-type calcium channels by terpenes derived from cannabis plants. A screen of eight commercially available terpenes revealed that camphene and alpha-bisabolol mediated partial, but significant inhibition of Cav3.2 channels expressed in tsA-201 cells, as well as native T-type channels in mouse dorsal root ganglion neurons. Both compounds inhibited peak current amplitude with IC50s in the low micromolar range, and mediated an additional small hyperpolarizing shift in half-inactivation voltage. When delivered intrathecally, both terpenes inhibited nocifensive responses in mice that had received an intraplantar injection of formalin, with alpha-bisabolol showing greater efficacy. Both terpenes reduced thermal hyperalgesia in mice injected with Complete Freund’s adjuvant. This effect was independent of sex, and absent in Cav3.2 null mice, indicating that these compounds mediate their analgesic properties by acting on Cav3.2 channels. Both compounds also inhibited mechanical hypersensitivity in a mouse model of neuropathic pain. Hence, camphene and alpha-bisabolol have a wide spectrum of analgesic action by virtue of inhibiting Cav3.2 T-type calcium channels.

Inhibition of human recombinant T‐type calcium channels by phytocannabinoids in vitro

“…Thus, concentrations of phytocannabinoids which modulate Ca V 3 channels in vitro can be achieved in vivo after oral administration of phytocannabinoid acids or plant extracts in which they are enriched, and this may provide a meaningful source of T-channel modulators devoid of at least some of the unwanted effects of THC-containing cannabis preparations. A further area to be explored is the potential interaction at T-type I Ca between Cannabis terpenoids and the phytocannabinoids examined here, as terpenoids alone also modulate these channels (El Alaoui et al, 2017;Gadotti et al, 2021). Cas et al, 2020;Suraev et al, 2018).…”

Central and peripheral contributions of T-type calcium channels in pain

“…In this context, one such DHP based T-type channel inhibitor was shown to attenuate both inflammatory and neuropathic pain in mice [ 128 ]. Similarly, the well-known cannabinoids delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) produce marked state-dependent inhibition of all T-type channels, but especially that of Ca v 3.1 and Ca v 3.2 [ 129 , 130 ]. The endogenous cannabinoid anandamide and some lipoamino acids have also shown efficacy in inhibiting T-type channels in vitro [ 131 – 133 ], along with several synthetic cannabinoid receptor agonists [ 131 , 134 ].…”

Plant and fungi derived analgesic natural products targeting voltage-gated sodium and calcium channels

“… Rescues NaV1.5 T353I plasma membrane expression. [ 44 ] Alpha-bisabolol Terpene Cannibus sativa ↓CaV3.2 ↓CaV3.3 ↓CaV2.1 Inhibited recombinant human CaV3.2 in HEK cells with IC 50 of 4.5 ± 1.1 μM [ 98 ] Astragalin Flavonol glycoside Roots of Astragalus membranaceus ↑L-type current Rat pancreatic islets tested with 100 µM. Hypoglycemic effect in hyperglycemic rats.…”

“… Sensory and motor block of rat sciatic nerve, tested with 0.375 to 0.75 mM. [ 46 ] Camphene Monoterpene Cannibus sativa ↓CaV3.2 ↓CaV3.3 ↓CaV2.1 Inhibited recombinant human CaV3.2 in HEK cells with IC 50 of 7.7 ± 1.8 μM [ 98 ] Cannabidiol, Δ9-tetrahydrocannabinol Benzoic acid Diterpenoid Cannabis sativa ↓CaV3.1–3.3 HEK cells tested with 10–30 μM. Mouse trigeminal ganglion neurons tested with 1 µM.…”

“…Recognizing that cannabinoids derived from cannabis [ 97 ] have analgesic properties, Gadotti et al screened eight terpenes that are also found in high concentrations in cannabis plants [ 98 ]. The cannabis-derived terpene alpha-bisabolol is present in essential oils and bubble gum products from cannabis cultivars and extracts.…”