Ion channels and pain: Important steps towards validating a new therapeutic target for neuropathic pain

Abstract

Acute pain is caused by noxious stimuli, and by stimuli that threaten to or cause tissue damage. Pain serves a crucial physiological function as a rapid warning system that can help prevent injury or limit the extent of damage. However, chronic pain, which is pain that persists after the initial noxious stimulus, tissue damage, and subsequent healing periods have passed, and is elicited by stimulus types or levels that do not normally elicit pain, is a major clinical challenge. Most chronic pain patients complain of a lack of complete relief from currently available drugs, and many of these drugs have adverse side effects. As such, there are intensive basic research and drug discovery efforts focused on developing better treatments for chronic pain (http://www.ninds.nih.gov/disorders/chronic_pain/chronic_pain.htm). One major form of chronic pain is neuropathic, in that it is based in the neurons involved in perception of pain, and the transduction, or processing of the resultant pain signals to the brain. Peripheral neuropathic pain is due to altered function and sensitization of neurons within the peripheral nociceptive system (i.e., nociceptive neurons), the sensory system responsible for the perception of pain and the transduction of pain signals to the spinal cord (http://www.iasppainorg/AM/Template.cfm?Section=Pain_Definitions.). A recent paper published in Experimental Neurology (Tsantoulas et al., 2014) identifies a novel contributor to peripheral neuropathic pain that may represent an attractive target for future drug discovery efforts aimed at ameliorating this form of chronic pain. Sensory ganglia such as trigeminal ganglia, and dorsal root ganglia (DRG), contain a variety of primary sensory neurons, with distinct morphologies and functions. Sensory neurons with medium and large diameter cell bodies have myelinated axons or A fibers that transduce signals from a variety of sensory modalities, and while those with small diameter cell bodies give rise to unmyelinated C fibers that transduce painful stimuli [reviewed in (Lawson, 2002)]. Within these major classes of neurons are those with a diversity of morphologies and functions, allowing for the selective discrimination of a wide variety of painful and non-painful stimuli. Within these neurons are the ion channels that underlie the fundamental steps of sensory transduction, namely the initiation of a propagating electrical signal at the sensory nerve endings in tissues, its conduction along the axon, and its transmission from the central terminals to neurons in the spinal cord [reviewed in (Gold and Gebhart, 2010)]. There are also a number of regulatory ion channels that shape diverse aspects of each of these events. When dysregulated, these ion channels that underlie the normal function of nociceptive neurons can contribute to the pathological states of neuropathic pain [reviewed in (Gold and Gebhart, 2010)]. The recent paper by Tsantoulas et al., (Tsantoulas et al., 2014) focuses on the role of a specific family of ion channels that serves as a critical component of the sensory transduction machinery in DRG neurons. The expression of these channels is reduced in an animal model of peripheral neuropathic pain. The authors were able to link this downregulation to a crucial aspect of peripheral neuropathic pain, the hyperexcitability of the nociceptive neurons that leads to ectopic transduction of pain signals to the spinal cord in the absence of a painful stimulus. This study not only identifies an important role for this particular class of ion channels, but also suggests that enhancing the activity of the remaining channels represents an attractive approach for future drug discovery efforts targeting neuropathic pain.