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

Harding, Erika K.; Zamponi, Gerald W.

doi:10.1186/s13041-022-00923-w

Cited by 36 publications

(29 citation statements)

References 160 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Future studies in preclinical epilepsy models are needed to assess whether GPR55 and T-type calcium channels are necessary for the anticonvulsant effect of these phytocannabinoids. It would also be interesting to explore the effects of these phytocannabinoids in other disease models in which T-type channels and GPR55 play a role, such as in models of insomnia, pain, and gastrointestinal disorders ( Harding and Zamponi, 2022 ). Given the promiscuity of the phytocannabinoids, additional cellular pharmacology studies are needed to address whether CBGVA and CBDVA affect other phytocannabinoid targets such as cannabinoid receptors and transient receptor potential (TRP) channels.…”

Section: Discussionmentioning

confidence: 99%

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

et al. 2022

View full text Add to dashboard Cite

Introduction: Cannabidiol (CBD) has been clinically approved for intractable epilepsies, offering hope that novel anticonvulsants in the phytocannabinoid class might be developed. Looking beyond CBD, we have recently reported that a series of biosynthetic precursor molecules found in cannabis display anticonvulsant properties. However, information on the pharmacological activities of these compounds on CNS drug targets is limited. The current study aimed to fill this knowledge gap by investigating whether anticonvulsant phytocannabinoids affect T-type calcium channels, which are known to modulate neuronal excitability, and may be relevant to the anti-seizure effects of this class of compounds.Materials and methods: A fluorescence-based assay was used to screen the ability of the phytocannabinoids to inhibit human T-type calcium channels overexpressed in HEK-293 cells. A subset of compounds was further examined using patch-clamp electrophysiology. Alphascreen technology was used to characterise selected compounds against G-protein coupled-receptor 55 (GPR55) overexpressed in HEK-293 cells, as GPR55 is another target of the phytocannabinoids.Results: A single 10 µM concentration screen in the fluorescence-based assay showed that phytocannabinoids inhibited T-type channels with substantial effects on Cav3.1 and Cav3.2 channels compared to the Cav3.3 channel. The anticonvulsant phytocannabinoids cannabigerovarinic acid (CBGVA) and cannabidivarinic acid (CBDVA) had the greatest magnitudes of effect (≥80% inhibition against Cav3.1 and Cav3.2), so were fully characterized in concentration-response studies. CBGVA and CBDVA had IC50 values of 6 μM and 2 µM on Cav3.1 channels; 2 μM and 11 µM on Cav3.2 channels, respectively. Biophysical studies at Cav3.1 showed that CBGVA caused a hyperpolarisation shift of steady-state inhibition. Both CBGVA and CBDVA had a use-dependent effect and preferentially inhibited Cav3.1 current in a slow inactivated state. CBGVA and CBDVA were also shown to antagonise GPR55.Conclusion and implications: These findings show that CBGVA and CBDVA inhibit T-type calcium channels and GPR55. These compounds should be further investigated to develop novel therapeutics for treating diseases associated with dysfunctional T-type channel activity.

show abstract

Section: Discussionmentioning

confidence: 99%

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Voltage‐gated calcium channels (VGCCs; Cas) are a promising target for the treatment of chronic pain due to their role in regulating neuronal excitability and facilitating synaptic vesicle release at primary afferent synapses (Harding & Zamponi, 2022). First‐order neurons transmit nociceptive information from peripheral tissue into the dorsal horn of the spinal cord, where neurotransmission onto dorsal horn neurons is predominantly facilitated by two presynaptic VGCCs: Ca v 2.2 (N‐type) and to a lesser extent Ca v 3.2 (T‐type) channels (Zamponi, 2016).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of Ca_v3.2 and Ca_v2.2 calcium channels by CB₁ receptors and cannabidiol

Harding

Souza

Gandini

et al. 2023

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

Background and Purpose: Cannabinoids are a promising therapeutic avenue for chronic pain. However, clinical trials often fail to report analgesic efficacy of cannabinoids. Inhibition of voltage gate calcium (Ca v ) channels is one mechanism through which cannabinoids may produce analgesia. We hypothesized that cannabinoids and cannabinoid receptor agonists target different types of Ca v channels through distinct mechanisms.Experimental Approach: Electrophysiological recordings from tsA-201 cells expressing either Ca v 3.2 or Ca v 2.2 were used to assess inhibition by HU-210 or cannabidiol (CBD) in the absence and presence of the CB 1 receptor. Homology modelling assessed potential interaction sites for CBD in both Ca v 2.2 and Ca v 3.2. Analgesic effects of CBD were assessed in mouse models of inflammatory and neuropathic pain.Key Results: HU-210 (1 μM) inhibited Ca v 2.2 function in the presence of CB 1 receptor but had no effect on Ca v 3.2 regardless of co-expression of CB 1 receptor. By contrast, CBD (3 μM) produced no inhibition of Ca v 2.2 and instead inhibited Ca v 3.2 independently of CB 1 receptors. Homology modelling supported these findings, indicating that CBD binds to and occludes the pore of Ca v 3.2, but not Ca v 2.2. Intrathecal CBD alleviated thermal and mechanical hypersensitivity in both male and female mice, and this effect was absent in Ca v 3.2 null mice. Conclusion and Implications: Our findings reveal differential modulation of Ca v 2.2 and Ca v 3.2 channels by CB 1 receptors and CBD. This advances our understanding of how different cannabinoids produce analgesia through action at different voltagegated calcium channels and could influence the development of novel cannabinoidbased therapeutics for treatment of chronic pain. K E Y W O R D S cannabidiol, cannabinoid receptor, CB 1 receptors, Ca v 2.2, Ca v 3.2, T-type calcium channel, voltage-gated calcium channel Abbreviations: CFA, Complete Freund's Adjuvant; DRG, dorsal root ganglion; tsA-201, transformed human kidney cell line expressing an SV40 temperature-sensitive T antigen; VGCC, voltagegated calcium channel.

show abstract

“…The T-type calcium Cav3.2 isoform regulates the neuronal response to pain. 52,53 Cav3.2 knockout models and mice pretreated with Cav3.2 blockers showed impaired nociceptive response to pain stimuli. 54 Previous reports indicated that the antinociceptive action of arachidonic compounds involves inhibition of Cav3.2 channels, suggesting a potential interaction between Cav3.2 and AM404.…”

Section: Downstream Targets Of Trpvmentioning

confidence: 99%

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Mallet¹,

Desmeules²,

Pegahi³

et al. 2023

JPR

View full text Add to dashboard Cite

Paracetamol remains the recommended first-line option for mild-to-moderate acute pain in general population and particularly in vulnerable populations. Despite its wide use, debate exists regarding the analgesic mechanism of action (MoA) of paracetamol. A growing body of evidence challenged the notion that paracetamol exerts its analgesic effect through cyclooxygenase (COX)-dependent inhibitory effect. It is now more evident that paracetamol analgesia has multiple pathways and is mediated by the formation of the bioactive AM404 metabolite in the central nervous system (CNS). AM404 is a potent activator of TRPV 1 , a major contributor to neuronal response to pain in the brain and dorsal horn. In the periaqueductal grey, the bioactive metabolite AM404 activated the TRPV 1 channel‐mGlu5 receptor‐PLC‐DAGL‐CB1 receptor signaling cascade. The present article provides a comprehensive literature review of the centrally located, COX-independent, analgesic MoA of paracetamol and relates how the current experimental evidence can be translated into clinical practice. The evidence discussed in this review established paracetamol as a central, COX-independent, antinociceptive medication that has a distinct MoA from non-steroidal anti-inflammatory drugs (NSAIDs) and a more tolerable safety profile. With the establishment of the central MoA of paracetamol, we believe that paracetamol remains the preferred first-line option for mild-to-moderate acute pain for healthy adults, children, and patients with health concerns. However, safety concerns remain with the high dose of paracetamol due to the NAPQI-mediated liver necrosis. Centrally acting paracetamol/ p -aminophenol derivatives could potentiate the analgesic effect of paracetamol without increasing the risk of hepatoxicity. Moreover, the specific central MoA of paracetamol allows its combination with other analgesics, including NSAIDs, with a different MoA. Future experiments to better explain the central actions of paracetamol could pave the way for discovering new central analgesics with a better benefit-to-risk ratio.

show abstract

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

Cited by 36 publications

References 160 publications

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

Differential regulation of Ca_v3.2 and Ca_v2.2 calcium channels by CB₁ receptors and cannabidiol

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Contact Info

Product

Resources

About

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

Cited by 36 publications

References 160 publications

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

The anticonvulsant phytocannabinoids CBGVA and CBDVA inhibit recombinant T-type channels

Differential regulation of Cav3.2 and Cav2.2 calcium channels by CB1 receptors and cannabidiol

An Updated Review on the Metabolite (AM404)-Mediated Central Mechanism of Action of Paracetamol (Acetaminophen): Experimental Evidence and Potential Clinical Impact

Contact Info

Product

Resources

About

Differential regulation of Ca_v3.2 and Ca_v2.2 calcium channels by CB₁ receptors and cannabidiol