Variations in the regulation of pain genes after nerve injury : with focus on sodium channels

Abstract

Chronic neuropathic pain is a burdensome clinical condition that causes major suffering for countless of individuals worldwide. It is characterized by a hyperreactive nervous system with hyperexcitable neurons that fire in the absence of stimuli or at mild stimuli, causing pain. Although the processes that lead to neuropathic pain are not yet fully understood, the insight into putative causative mechanisms has increased vastly in recent years. Much of the research in the field has focused on the voltage-gated sodium channels (VGSC). These are ion channels that activate in response to membrane depolarizations and initiate and propagate electrical impulses. Thus, regardless of what other mechanisms that may contribute to the changed neuronal phenotype after injury, in the end, it is the VGSC that carry out the electrical nerve impulses. This makes them attractive candidate targets for pain alleviating drug development. Our data on the expression of VGSC in the dorsal root ganglion (DRG) of a damaged nerve implies that these channels are indeed involved in pain development after nerve injury. In particular, we found a correlation of expression data on Nav1.6 and Nav1.9 with spontaneous pain in the neuroma model (autotomy). These two channels have distinct distribution pattern and electrophysiological properties and thus may contribute in separate ways to the formation of hyperexcitable neurons. Some of our data also suggest that Contactin, a molecule involved in trafficking of the sodium channels to the cell membrane, may contribute to a pain phenotype.

The majority of neuropathic pain conditions are seen at spinal level compared to the less frequent orofacial neuropathic pain states. For this reason, most experimental pain studies are carried out in the lumbar DRG region. Most probably, much data obtained from these studies are also relevant to studies of orofacial pain. However, it is now clear that the pathophysiology of the trigeminal nerve in many ways differ to that of spinal nerves. Thus, there is a need for pain models specifically adapted to the trigeminal system when studying neuropathic orofacial pain. Here, a novel model for trigeminal neuropathic pain was presented. The model involves a photochemically-induced ischemic injury to the infraorbital branch of the trigeminal nerve. VGSC were expressed and regulated in the affected trigeminal ganglion (TG) in a similar fashion as seen in the DRG. Thus, new effective pharmaceutical agents that target VGSC in chronic pain at spinal levels should be useful against orofacial neuropathic pain conditions as well.

In addition to VGSC, other molecules are likely to be involved in neuropathic pain. After peripheral nerve injury, a vast number of genes are regulated in the affected DRG leading to a changed composition of receptors, ion channels, neurotransmitters etc. in the neuron. It is yet to be found out which of these changes that are related to neuropathic pain. Against this background, we performed a genome-wide search for regulated genes in five inbred mouse strains with distinct pain phenotypes after nerve injury. Subsequently, expression data for each of the regulated genes was correlated against pain phenotypes. This yielded three gene lists, each associated with one of the phenotypes mechanical hypersensitivity, thermal hypersensitivity and spontaneous pain in the neuroma model. These lists need further refinement in order to find specific pain genes, but may, at this stage, serve as look-up tables for genes whose regulation likely contributes to pain variability.