Pathophysiological implication of Ca V 3.1 T-type Ca 2+ channels in trigeminal neuropathic pain

Section: Small Organic Molecules Targeting T‐type Calcium Channels Asmentioning

confidence: 99%

Recent advances in the development of T‐type calcium channel blockers for pain intervention

Snutch

Zamponi

2017

“…Additionally, Ca v 3.2 knockin/flox studies marked their relevance in setting up the firing threshold of low‐threshold mechanoreceptors (LTMRs) Aδ‐ and C‐LTMRs (Francois et al, ); whereas genetic ablation of Ca v 3.2 in C‐LTMRs validates their role in the noxious mechanical cold, light‐touch, and chemical perception that underlie various forms of neuropathic pain. Although Ca v 3.1 channels have been less explored, this isoform was recently implicated in the pathophysiology of trigeminal neuropathic pain (Choi, Yu, Hwang, & Llinas, ).…”

Section: Introductionmentioning

confidence: 99%

“…Ca v 3.1 channels have been less explored, this isoform was recently implicated in the pathophysiology of trigeminal neuropathic pain (Choi, Yu, Hwang, & Llinas, 2016).…”

mentioning

confidence: 99%

Analgesic transient receptor potential vanilloid‐1‐active compounds inhibit native and recombinant T‐type calcium channels

McArthur

Finol‐Urdaneta

Adams

2019

Background and Purpose T‐type calcium (Cav3) and transient receptor potential vanilloid‐1 (TRPV1) channels play central roles in the control of excitability in the peripheral nervous system and are regarded as potential therapeutic pain targets. Modulators that either activate or inhibit TRPV1‐mediated currents display analgesic properties in various pain models despite opposing effects on their connate target, TRPV1. We explored the effects of TRPV1‐active compounds on Cav3‐mediated currents. Experimental Approach Whole‐cell patch clamp recordings were used to examine the effects of TRPV1‐active compounds on rat dorsal root ganglion low voltage‐activated calcium currents and recombinant Cav3 isoforms in expression systems. Key Results The classical TRPV1 agonist capsaicin as well as TRPV1 antagonists A‐889425, BCTC, and capsazepine directly inhibited Cav3 channels. These compounds altered the voltage‐dependence of activation and inactivation of Cav3 channels and delayed their recovery from inactivation, leading to a concomitant decrease in T‐type current availability. The TRPV1 antagonist capsazepine potently inhibited Cav3.1 and 3.2 channels (KD < 120 nM), as demonstrated by its slow off rate. In contrast, neither the TRPV1 agonists, Palvanil and resiniferatoxin, nor the TRPV1 antagonist AMG9810 modulated Cav3‐mediated currents. Conclusions and Implications Analgesic TRPV1‐active compounds inhibit Cav3 currents in native and heterologous systems. Hence, their analgesic effects may not be exclusively attributed to their actions on TRPV1, which has important implications in the current understanding of nociceptive pathways. Importantly, our results highlight the need for attention in the experimental design used to address the analgesic properties of Cav3 channel inhibitors.

“…In agreement, no central side effect was detected when the toxin was locally injected to mice for studying its action on neuromuscular system and on heat and tactile sensitivity, in vivo. In addition, the analgesic property of CyrTx-1a seems not to be associated with inhibition of hCa V 3.1 and hCa V 3.2, two channels known to be involved in pain process (Choi, Yu, Hwang, & Llinas, 2016;Sekiguchi, Tsubota, & Kawabata, 2018). Moreover, the synthetic peptide has low, at best micromolar, affinities for hNa V 1.5, hCa V 1.2, hK V 7.1, hK V 11.1, and hKir2.1 channels, well-known targets in cardiac safety (Crumb, Vicente, Johannesen, & Strauss, 2016).…”

Section: Effects Of Cyrtx-1a Compared To Hwtx-iv On the Mouse Neumentioning

confidence: 91%

From identification to functional characterization of cyriotoxin‐1a, an antinociceptive toxin from the spider Cyriopagopus schioedtei

Gonçalves

Benoit

Kurz

et al. 2019

Background and Purpose:The Na V 1.7 channel is highly expressed in dorsal root ganglia of the sensory nervous system and plays a central role in the pain signalling process. We investigated a library prepared from original venoms of 117 different animals to identify new selective inhibitors of this target.Experimental Approach: We used high throughput screening of a large venom collection using automated patch-clamp experiments on human voltage-gated sodium channel subtypes and then in vitro and in vivo electrophysiological experiments to characterize the active peptides that have been purified, sequenced, and chemically synthesized. Analgesic effects were evaluated in vivo in mice models.Key Results: We identified cyriotoxin-1a (CyrTx-1a), a novel peptide isolated from Cyriopagopus schioedtei spider venom, as a candidate for further characterization. This 33 amino acids toxin belongs to the inhibitor cystine knot structural family and inhibits hNa V 1.1-1.3 and 1.6-1.7 channels in the low nanomolar range, compared to the micromolar range for hNa V 1.4-1.5 and 1.8 channels. CyrTx-1a was 920 times more efficient at inhibiting tetrodotoxin (TTX)-sensitive than TTX-resistant sodium currents recorded from adult mouse dorsal root ganglia neurons and in vivo electrophysiological experiments showed that CyrTx-1a was approximately 170 times less efficient than huwentoxin-IV at altering mouse skeletal neuromuscular excitability properties. CyrTx-1a exhibited an analgesic effect in mice by increasing reaction time in the hot-plate assay. Conclusions and Implications:The pharmacological profile of CyrTx-1a paves the way for further molecular engineering aimed to optimize the potential antinociceptive properties of this peptide.