New targets for neuropathic pain therapeutics

Abstract

Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional 'small-molecule' approach.

Involvement of Nav 1.8 sodium ion channels in the transduction of mechanical pain in a rodent model of osteoarthritis

“…The clear disadvantages of using non-selective sodium channel blockers locally are complete loss of sensation and disruption of normal physiological functions such as proprioception and neurovasoregulation. Systemic use of such blockers can lead to cardiotoxicity, sedation and cognitive impairment [32]. Targeting sodium channels which are located exclusively on nociceptive afferents could reduce these undesirable side effects.…”

Identification of Farnesyl Pyrophosphate and N-Arachidonylglycine as Endogenous Ligands for GPR92

“…This observation, together with coexpression of GPR92 and TRPV1, indicates a possible role of GPR92 in TRPV1-medicated pain sensing. Recently involvement of GPR92 in neuropathic pain has been suggested because GPR92 knock-out mice display significantly less sensitivity in the spinal cord to noxious mechanical and thermal stimulation than wild type littermates (28).…”

Aiming drug discovery at lysophosphatidic acid targets

“…Analysis of LPA 5 is currently limited to heterologous expression studies, and experiments using farnesyl phosphate as a selective, although not a specific, agonist. LPA 5 knockout mice have deficits in the response to neuropathic pain (Sheardown et al ., 2004; Kinloch and Cox, 2005). LPA 5 ‐lacZ reporter gene‐expressing mice showed the strongest expression in cell bodies of dorsal root ganglion cells that extend C‐fibres (sensory nerves conveying pain signals) but not in those neurons with Aβ fibres (sensory nerves conveying non‐pain signals).…”

“…There was, however, a significant delay in the tail flick test, indicating impaired nociceptive function. In vivo electrophysiological recordings (Kinloch and Cox, 2005) from the dorsal horn of mutant animals revealed significantly lower numbers of action potentials in response to noxious mechanical, thermal and cold stimuli applied to the hind foot than in wild‐type mice. However, there was no difference in the number of action potentials recorded in response to non‐noxious brush stimulation or to temperature in the non‐noxious range.…”