title: Design and assessment of a potent sodium channel blocking derivative of mexiletine for minimizing experimental neuropathic pain in several rat models.
abstract: Physical or chemical damage to peripheral nerves can result in neuropathic pain which is not easily alleviated by conventional analgesic drugs. Substantial evidence has demonstrated that voltage-gated Na+ channels in the membrane of damaged nerves play a key role in the establishment and maintenance of pathological neuronal excitability not only of these peripheral nerves but also in the second- and third-order neurons in the pain pathway to the cerebral cortex. Na+ channel blocking drugs have been used in treating neuropathic pain with limited success mainly because of a preponderance of side-effects. We have developed an analogue of mexiletine which is approximately 80 times more potent than mexiletine in competing with the radioligand, 3H-batrachotoxinin for binding to Na+ channels in rat brain membranes and also it is much more lipophilic than mexiletine which should enhance its uptake into the brain to block the increased expression of Na+ channels on second- and third-order neurons of the pain pathway. This analogue, HFI-1, has been tested in three different rat models of neuropathic pain (formalin paw model, ligated spinal nerve model and contusive spinal cord injury model) and found to be more effective in reducing pain behaviours than mexiletine.
authors.affiliation: Howard Florey Institute, University of Melbourne, Parkville, VIC 3010, Australia.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weston
authors.forename: Kamani R
authors.initials: KR
authors.lastname: Subasinghe
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Staikopoulos
authors.forename: Bevyn
authors.initials: B
authors.lastname: Jarrott
mesh_terms: D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D055808:Drug Discovery / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008297:Male; D008801:Mexiletine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015222:Sodium Channels / Q000378:metabolism* / Q000502:physiology
chemical_list: D000700:Analgesics; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D008801:Mexiletine