University of Wollongong
Browse

Cyclic analogues of α-conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain

Download (1.64 MB)
journal contribution
posted on 2024-11-16, 03:15 authored by Joel Castro, Luke Grundy, Annemie Deiteren, Andrea M Harrington, Tracey O'Donnell, Jessica Maddern, Jessi Moore, Sonia Garcia-Caraballo, Grigori Rychkov, Rilei Yu, Quentin Kaas, David J Craik, David AdamsDavid Adams, Stuart Brierley
Background and Purpose: Patients with irritable bowel syndrome suffer from chronic visceral pain (CVP) and limited analgesic therapeutic options are currently available. We have shown that α-conotoxin Vc1.1 induced activation of GABAB receptors on the peripheral endings of colonic afferents and reduced nociceptive signalling from the viscera. However, the analgesic efficacy of more stable, cyclized versions of Vc1.1 on CVP remains to be determined. Experimental Approach: Using ex vivo colonic afferent preparations from mice, we determined the inhibitory actions of cyclized Vc1.1 (cVc1.1) and two cVc1.1 analogues on mouse colonic nociceptors in healthy and chronic visceral hypersensitivity (CVH) states. Using whole-cell patch clamp recordings, we also assessed the inhibitory actions of these peptides on the neuronal excitability of colonic innervating dorsal root ganglion neurons. In vivo, the analgesic efficacy of these analogues was assessed by determining the visceromotor response to colorectal distension in healthy and CVH mice. Key Results: cVc1.1 and the cVc1.1 analogues, [C2H,C8F]cVc1.1 and [N9W] cVc1.1, all caused concentration-dependent inhibition of colonic nociceptors from healthy mice. Inhibition by these peptides was greater than those evoked by linear Vc1.1 and was substantially greater in colonic nociceptors from CVH mice. cVc1.1 also reduced excitability of colonic dorsal root ganglion neurons, with greater effect in CVH neurons. CVH mice treated with cVc1.1 intra-colonically displayed reduced pain responses to noxious colorectal distension compared with vehicle-treated CVH mice. Conclusions and Implications: Cyclic versions of Vc1.1 evoked significant anti-nociceptive actions in CVH states, suggesting that they could be novel candidates for treatment of CVP.

Funding

GABA(B) Receptor Modulation of Gastrointestinal Function in Health and Disease by Alpha-Conotoxins

National Health and Medical Research Council

Find out more...

History

Citation

Castro, J., Grundy, L., Deiteren, A., Harrington, A. M., O'Donnell, T., Maddern, J., Moore, J., Garcia-Caraballo, S., Rychkov, G. Y., Yu, R., Kaas, Q., Craik, D. J., Adams, D. J. & Brierley, S. M. (2018). Cyclic analogues of α-conotoxin Vc1.1 inhibit colonic nociceptors and provide analgesia in a mouse model of chronic abdominal pain. British Journal of Pharmacology, 175 (12), 2384-2398.

Journal title

British Journal of Pharmacology

Volume

175

Issue

12

Pagination

2384-2398

Language

English

RIS ID

122196

Usage metrics

    Categories

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC