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.
Highlights
Cav3.2 T-type calcium channels are important mediators of nociceptive signalling in the primary afferent pain pathway [1, 2] by regulating affent fiber and spinal cord interneuron activity, and synaptic communication in the spinal cord [3,4,5,6,7]
Cannabis derived terpenes inhibit Cav3.2 channels We tested the inhibitory actions of eight commercially available terpenes on human Cav3.2 calcium channels transiently expressed in tsA-201 cells using whole cell patch clamp
Camphene and alpha-bisabolol were tested on transiently expressed Cav3.1 and Cav3.3 T-type channels (Fig. 1c), revealing that these terpenes block all of these channels, albeit to varying extent with Cav3.3 being the least affected
Summary
Cav3.2 T-type calcium channels are important mediators of nociceptive signalling in the primary afferent pain pathway [1, 2] by regulating affent fiber and spinal cord interneuron activity, and synaptic communication in the spinal cord [3,4,5,6,7]. Cav3.2 calcium channels can be inhibited by certain types of synthetic cannabinoids [23, 24] They are potently blocked the endocannabinoids anandamide and N-arachidonoyl glycine [25, 26], suggesting the possibility that the analgesic actions of these endocannabinoids may at least in part be due to inhibition of T-type calcium channels. This is supported by a study by Barbara and colleagues [27] who attributed the analgesic effects of certain endocannabinoids to T-type calcium channel inhibition.
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