Anti-allodynic efficacy of the chi-conopeptide, Xen2174, in rats with neuropathic pain.
Xen2174 is a structural analogue of Mr1A, a chi-conopeptide recently isolated from the venom of the marine cone snail, Conus marmoreus. Although both chi-conopeptides are highly selective inhibitors of the norepinephrine transporter (NET), Xen2174 has superior chemical stability relative to Mr1A. It is well-known that tricyclic antidepressants (TCAs) are also potent NET inhibitors, but their poor selectivity relative to other monoamine transporters and various G-protein-coupled receptors, results in dose-limiting side-effects in vivo. As TCAs and the alpha(2)-adrenoceptor agonist, clonidine, have established efficacy for the relief of neuropathic pain, this study examined whether intrathecal (i.t.) Xen2174 alleviated mechanical allodynia in rats with either a chronic constriction injury of the sciatic nerve (CCI-rats) or an L5/L6 spinal-nerve injury. The anti-allodynic responses of i.t. Mr1A and i.t. morphine were also investigated in CCI-rats. Paw withdrawal thresholds were assessed using calibrated von Frey filaments. Bolus doses of i.t. Xen2174 produced dose-dependent relief of mechanical allodynia in CCI-rats and in spinal nerve-ligated rats. Dose-dependent anti-allodynic effects were also produced by i.t. bolus doses of Mr1A and morphine in CCI-rats, but a pronounced 'ceiling' effect was observed for i.t. morphine. The side-effect profiles were mild for both chi-conopeptides with an absence of sedation. Confirming the noradrenergic mechanism of action, i.t. co-administration of yohimbine (100 nmol) with Xen2174 (10 nmol) abolished Xen2174s anti-allodynic actions. Xen2174 appears to be a promising candidate for development as a novel therapeutic for i.t. administration to patients with persistent neuropathic pain.
Nielsen
Carsten K
CK
School of Pharmacy, The University of Queensland, Brisbane, Qld, Australia.
Lewis
Richard J
RJ
Alewood
Dianne
D
Drinkwater
Roger
R
Palant
Elka
E
Patterson
Margaret
M
Yaksh
Tony L
TL
McCumber
Damon
D
Smith
Maree T
MT
D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D020916:Conotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use; D009437:Neuralgia / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D013127:Spinal Nerves / Q000503:physiopathology
D000701:Analgesics, Opioid; D020916:Conotoxins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010455:Peptides; C500187:Xen2174; C507563:chi-conopeptide MrIA, Conus; D009020:Morphine