Abstract
Neuropathic pain remains notoriously difficult to treat despite numerous drug targets. Here, we offer a novel explanation for this intractability. Computer simulations predicted that qualitative changes in primary afferent excitability linked to neuropathic pain arise through a switch in spike initiation dynamics when molecular pathologies reach a tipping point (criticality), and that this tipping point can be reached via several different molecular pathologies (degeneracy). We experimentally tested these predictions by pharmacologically blocking native conductances and/or electrophysiologically inserting virtual conductances. Multiple different manipulations successfully reproduced or reversed neuropathic changes in primary afferents from naïve or nerve-injured rats, respectively, thus confirming the predicted criticality and its degenerate basis. Degeneracy means that several different molecular pathologies are individually sufficient to cause hyperexcitability, and because several such pathologies co-occur after nerve injury, that no single pathology is uniquely necessary. Consequently, single-target-drugs can be circumvented by maladaptive plasticity in any one of several ion channels. DOI: http://dx.doi.org/10.7554/eLife.02370.001.
Highlights
Neuropathic pain—pain arising from damage to or dysfunction of the nervous system (Merskey and Bogduk, 1994)—is notoriously difficult to treat
We derived the voltage-dependency and kinetics (Figure 1A) for an additional conductance (Equations 1–4 in ‘Materials and methods’) which, when added to our base model, modulates its spike initiation dynamics. This conductance corresponds to either a sodium or potassium channel depending on its associated reversal potential and, according to our analysis, must be active at subthreshold voltages. The parameters for this conductance were chosen to modulate spike initiation dynamics, not to model specific ion channel types that are known to be altered by nerve injury
Using computer simulations and experiments, we have demonstrated that primary afferent hyperexcitability associated with neuropathic pain arises through a switch in spike initiation dynamics that occurs when neurons cross a tipping point
Summary
Neuropathic pain—pain arising from damage to or dysfunction of the nervous system (Merskey and Bogduk, 1994)—is notoriously difficult to treat. An alternative possibility is that degeneracy within the pain system allows the pathogenic process to circumvent single-target-drugs. Degeneracy refers to multiple ‘different’ mechanisms conveying equivalent function (Edelman and Gally, 2001); by comparison, redundancy refers to multiple instantiations of the ‘same’ mechanism. Both convey robustness to complex systems (Kitano, 2004a). Degeneracy is recognized as an important factor for cancer and other complex diseases (Kitano, 2004a, 2004b; Tian et al, 2011), including epilepsy (Klassen et al, 2011) but has yet to inform pain research or analgesic drug development. Degeneracy has been recognized in neural systems (Prinz et al, 2004) and its existence and functional implications are gaining increasing attention (Grashow et al, 2009, 2010; Marder, 2011; Amendola et al, 2012; Zhao and Golowasch, 2012; Gutierrez et al, 2013; O’Leary et al, 2013; Ransdell et al, 2013)
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