Journal of Clinical & Experimental Pharmacology

Increased Expression of HCN2 Channel Protein in L4 Dorsal Root Ganglion Neurons Following Axotomy of L5 Spinal Nerve Injury: Possible Role in Peripheral Neuropthic Pain

3^rd World Congress on Pharmacology

August 08-10, 2016 Birmingham, UK

Martin Smith, Laiche Djouhri

Wolfson CARD, King�??s College London, London, SE1 1UL, U.K.
Department of Physiology, College of Medicine, King Saud University, P.O. Box 7805, Riyadh 11472, Saudi Arabia

Posters & Accepted Abstracts: Clin Exp Pharmacol

Abstract:

Peripheral neuropathic pain (PNP) is characterized by chronic spontaneous pain and/or hypersensitivity to normally painful or nonpainful stimuli. This pain results partly from abnormal hyper excitability of dorsal root ganglion (DRG) neurons that convey sensory information from the periphery to the central nervous system. Previous studies have shown, using a modified version of the lumbar 5 (L5)-spinal nerve ligation model of PNP (model is termed mSNA and involves L5-spinal nerve taxonomy plus loose ligation of the lumbar 4 (L4)-spinal nerve with neuro inflammation-inducing chromic-gut), that L4 DRG neurons exhibit increased spontaneous activity, the key characteristic of aberrant neuronal hyper excitability. However, the underlying ionic and molecular mechanisms of the hyper excitability of L4 DRG neurons are incompletely understood resulting in difficulty treating this condition in patients. This hyper excitability could result from changes in expression and/or function of ion channels including the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (composed of HCN1-HCN4 subunits), which are active near the neuron�??s resting membrane potential and produce an excitatory inward current that depolarizes the membrane potential making the generation of an individual action potential more likely. In this presentation, data will be discussed suggesting a role for HCN channels in hypersensitivity associated PNP. The data were obtained from studies performed in a rat model of PNP, and aimed at examining whether: (a) expression of HCN1�??HCN3 channels is altered in L4 DRG neurons which are essential for transmission of evoked pain in the mSNA model and which contribute to chronic spontaneous pain, and (b) local (intraplantar) blockade of these HCN channels, with a specific blocker, ZD7288, attenuates chronic spontaneous pain and/or evoked pain. The findings of these studies revealed: (1) a significant increase in HCN2-immunoreactivity in small (<30 μm) DRG neurons (predominantly IB4-negative neurons), and in the proportion of small neurons expressing HCN2 (putative nociceptors); (2) no significant change in HCN1- or HCN3-immunoreactivity in all cell types; and (3) attenuation, with ZD7288 (100 μM intraplantar), of chronic spontaneous pain behavior (spontaneous foot lifting) and mechanical, but not, heat hypersensitivity. The results suggest that peripheral HCN channels are involved in the mechanisms of spinal nerve injury-induced PNP, and that HCN channels, possibly HCN2, represent a novel target for PNP treatment. The findings are consistent with those of previous studies suggesting a pivotal role for HCN channels, specifically HCN2, in chronic inflammatory and neuropathic pain that afflicts a vast number of patients across the globe.

Biography :

Email: martin.smith@kcl.ac.uk