Anti-allodynic efficacy of the χ-conopeptide, Xen2174, in rats with neuropathic pain

• Published in: Pain (Amsterdam) Vol. 118; no. 1; pp. 112 - 124
• Main Authors: Nielsen, Carsten K., Lewis, Richard J., Alewood, Dianne, Drinkwater, Roger, Palant, Elka, Patterson, Margaret, Yaksh, Tony L., McCumber, Damon, Smith, Maree T.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01-11-2005; Elsevier
• Subjects: Analgesics, Opioid - pharmacology; Analgesics, Opioid - therapeutic use; Animals; Biological and medical sciences; Conotoxins - pharmacology; Conotoxins - therapeutic use; Conus marmoreus; Cranial nerves. Spinal roots. Peripheral nerves. Autonomic nervous system. Gustation. Olfaction; Disease Models, Animal; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Illness and personality; Illness, stress and coping; Injections, Spinal; L5/L6 nerve ligation; Male; Medical sciences; Morphine; Morphine - pharmacology; Morphine - therapeutic use; Nervous system (semeiology, syndromes); Neuralgia - drug therapy; Neuralgia - physiopathology; Neuralgia - prevention & control; Neurology; Norepinephrine Plasma Membrane Transport Proteins - drug effects; Norepinephrine Plasma Membrane Transport Proteins - physiology; Peptides - pharmacology; Peptides - therapeutic use; Physical Stimulation; Psychology and medicine; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rat model of neuropathic pain: chronic constriction injury (CCI); Rats; Rats, Sprague-Dawley; Sciatic Neuropathy - drug therapy; Sciatic Neuropathy - physiopathology; Sciatic Neuropathy - prevention & control; Spinal Nerves - physiopathology; Tactile allodynia; Von Frey filaments; X-conopeptides: intrathecal dosing; Morphine; L5/L6 nerve ligation; Tactile allodynia; Von Frey filaments; Rat model of neuropathic pain: chronic constriction injury (CCI); X-conopeptides: intrathecal dosing; Rat; Chemical stability; Selectivity; chronic constriction injury (CCI); Peripheral neuropathy; Rat model of neuropathic pain; Spinal nerve; Pain; Clonidine; Peripheral nerve disease; G protein; Biological receptor; Allodynia; Human; α2-Adrenergic receptor; Nervous system diseases; Rodentia; Catecholamine; X-conopeptides; Vertebrata; Mammalia; Venom; Norepinephrine; Sciatic nerve; intrathecal dosing
• ISSN: 0304-3959; 1872-6623
• DOI: 10.1016/j.pain.2005.08.002

Xen2174 is a structural analogue of Mr1A, a χ-conopeptide recently isolated from the venom of the marine cone snail,
Conus marmoreus. Although both χ-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 α
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 χ-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 Xen2174
s 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.