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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