Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy
Graphical abstract
Introduction
Neuropathic pain refers to pain caused by damage to or dysfunction of the nervous system [1]. It has several etiologies including trauma (e.g. nerve compression, spinal cord injury), disease (e.g. diabetes, multiple sclerosis) and toxicity (e.g. chemotherapeutic and antiretroviral agents). Unlike nociceptive pain, which is evoked by noxious stimuli, neuropathic pain is characterized by spontaneous pain and hypersensitivity to innocuous tactile and thermal stimuli. These sensory disturbances arise from changes, including neuronal hyperexcitability, that develop at multiple points along the neuraxis [2]. In many cases, excessive input from the periphery is necessary and sufficient to produce neuropathic pain [3, 4, 5], which suggests that neuropathic pain can be effectively treated by reversing primary afferent hyperexcitability. Significant research has been directed toward deciphering how afferent excitability is altered by nerve injury and which ion channels are involved, but these efforts have yet to yield clinically effective treatments [6, 7]. This prompts the question of whether we are on the right track and have simply not yet reached the desired translational outcomes, or whether an unappreciated factor is impeding progress. We will argue in favor of the latter explanation.
The ion channels involved in pain processing by primary afferent neurons have been comprehensively reviewed elsewhere [4, 8•, 9]. Here, we will focus on demonstrating that changes in diverse ion channels can produce similar patterns of cellular hyperexcitability and that many ion channel changes co-develop after nerve injury. Co-development of distinct molecular changes capable of producing equivalent cellular hyperexcitability is an example of degeneracy. Degeneracy means that an outcome does not have a unique basis [10••]. Degenerate processes — distinct processes that produce equivalent outcomes — confer robust phenotypes because disruption of any one process is compensated for by other processes [11, 12••, 13]. Robustness of a healthy phenotype is desirable but degeneracy may be co-opted under pathological conditions, stabilizing the pathological phenotype and thus rendering neuropathic pain refractory to treatment. The importance of degeneracy and robustness is gaining recognition in fields like cancer [14•] and infectious diseases [15], but has escaped the attention of pain researchers.
Section snippets
Primary afferent hyperexcitability and the ion channels responsible for it
Primary afferents are the first-order sensory neurons that relay sensory information from peripheral tissue to the central nervous system. Afferents are heterogeneous [16, 17]. Nociceptive sensory information is normally conveyed by unmyelinated C fibers and thinly myelinated Aδ fibers [18] but, under pathological conditions, activation of thickly myelinated Aβ fibers can produce pain in the form of mechanical allodynia (i.e. hypersensitivity to light touch) [19]. Contrary to labeled lines in
The causal link between ion channel changes and cellular hyperexcitability
Although nerve injury may induce hyperexcitability and alter the expression or function of a certain ion channel, the ion channel change may not cause (or contribute in any way to) the hyperexcitability. In this regard, many studies provide only correlational links between molecular changes and cellular hyperexcitability. To test if an ion channel is necessary for hyperexcitability, one must selectively block its function or reduce/eliminate its expression. Notably, an ion channel may be
NaV1.7 as a case study for choosing a drug target
Rare genetic disorders stemming from mutation of a single gene implicate particular ion channels in pain processing. For example, mutations causing a leftward (hyperpolarizing) shift in the voltage-dependent activation of NaV1.7 channels produce inherited erythromelalgia [48] and other mutations affecting inactivation of this same ion channel produce paroxysmal extreme pain disorder [49]. These phenotypes indicate that certain changes in NaV1.7 are sufficient to cause pain. Electrophysiological
The pathogenesis of hyperexcitability and its implications for degeneracy
Excitability is a complex phenotype that depends on nonlinear interactions between ion channels. Protein-protein interactions, whether direct or indirect, are quite limited compared with the large numbers of ion channels that can interact functionally by virtue of their mutual sensitivity to membrane potential. It is, therefore, not surprising that excitability is highly degenerate. This degeneracy allows excitability to be robustly regulated since the cell can readily adapt to disturbances in
Conclusions and outlook
Diverse ion channels are implicated in pain processing. Many of those channels are altered under the pathological conditions leading to neuropathic pain. The changes occurring in each channel cannot be considered in isolation from the changes occurring in other channels, or in isolation from the unchanged ion channels present in each neuron. This runs counter to reductionist tendencies, but taking a more integrative approach is crucial if we seek to fully understand how neurons control their
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Conflict of interest statement
Nothing declared.
Acknowledgements
This work was supported by a Discovery Grant from the Natural Sciences and Engineering Research Council of Canada, a New Investigator Award from the Canadian Institutes of Health Research, and an Ontario Early Researcher Award.
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