Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source

Weir, G. A. , Middleton, S. J., Clark, A. J., Daniel, T., Khovanov, N., McMahon, S. B. and Bennett, D. L. (2017) Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source. Brain, 140(10), pp. 2570-2585. (doi: 10.1093/brain/awx201) (PMID:28969375) (PMCID:PMC5841150)

Abstract

Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.

• Item Type: Articles
• Additional Information: D.L.B. is a senior Wellcome clinical scientist (202747/Z/16/Z). D.L.B., N.K., S.B.M. and G.A.W. are members of the Wellcome pain consortium (102645). S.J.M. is a student in the OXION programme funded by the Wellcome (109116/Z/15/Z). This work was partly funded by the European Union's Horizon 2020 research and innovation programme under grant agreement No 633491 (DOLORisk).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Weir, Dr Gregory
• Authors: Weir, G. A., Middleton, S. J., Clark, A. J., Daniel, T., Khovanov, N., McMahon, S. B., and Bennett, D. L.
• College/School: College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
• Journal Name: Brain
• Publisher: Oxford University Press
• ISSN: 0006-8950
• ISSN (Online): 1460-2156
• Published Online: 19 August 2017
• Copyright Holders: Copyright © 2017 The Authors
• First Published: First published in Brain 140(10): 2570-2585
• Publisher Policy: Reproduced under a Creative Commons License