Afferent hyperexcitability in neuropathic pain and the inconvenient truth about its degeneracy

•Hyperexcitability of primary somatosensory afferents leads to neuropathic pain.•Nerve damage causes changes in the expression or function of numerous ion channels.•Many distinct channel changes are individually sufficient to cause hyperexcitability.•This degeneracy means that no single change is necessary for hyperexcitability.•Degeneracy helps explain why afferent hyperexcitability is refractory to treatment.

Neuropathic pain, which arises from damage to the nervous system, is a major unmet clinical challenge. Reversing the neuronal hyperexcitability induced by nerve damage is a logical treatment strategy but has proven frustratingly difficult. Here, we propose a novel explanation for that difficulty. Changes in several different ion channels are individually sufficient to cause hyperexcitability in primary somatosensory neurons. Despite offering multiple drug targets, this scenario is problematic: if multiple sufficient changes are triggered by nerve injury, then no single change is necessary for hyperexcitability. This so-called degeneracy compromises therapeutic interventions because drug effects on any one ion channel can be circumvented by changes occurring in other ion channels. Overcoming degeneracy demands a more integrative approach to drug discovery.

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