Pain is a massive problem, particularly amongst the elderly. The revolution in molecular genetics in the late twentieth century coupled with recent advances in protein structure determination has provided powerful insights into how pain works, as well as identifying analgesic drug targets. Peripheral sodium channels are plausible candidates. Today I will discuss recent successes with drugs targeting a voltage-gated sodium channel (NaV1.8), found only in the peripheral nervous system. NaV1.8 mutations have been linked to both pain and cardiovascular problems - even sudden death. The discovery of a role for a small C-terminal fragment of NaV1.8 in cardiac function enables drugs that avoid actions on the heart to be developed. A new orally active drug named Journavx or Suzetrigine is now in the clinic and promises to improve present pain treatment.
In terms of human validation, the sodium channel NaV1.7 is a more compelling target. Humans lacking NaV1.7 are apparently normal but pain-free. However, embyonic pain-free humans and mice lacking NaV1.7 show a distinct mechanism of analgesia from adult knock-out animals. Intriguingly, embryonic NaV1.7 gene deletion enhances endogenous opioid signalling in peripheral neurons, resulting in diminished neurotransmitter release. In contrast, adult gene deletion or channel blocking drugs diminish excitability. NaV1.7 is expressed broadly within the central nervous system, as well as in the autonomic nervous system and some non- neuronal tissues such as the pancreas. Small molecule drug side effects are always a problem, and the broad role of NaV1.7 particularly in the autonomic nervous system means that antagonists of NaV1.7 are toxic . In contrast, the interaction with the opioid system in embryonic nulls presents a fascinating potential new route to pain treatment.
As well as targeting ion channels, the cell populations expressing particular ion channels can be useful analgesic targets. Chemogenetic silencing of neurons expressing NaV1.8 is a highly effective route to causing analgesia in preclinical studies. In addition, neuro-immune interactions can be interrogated through studies of neuron-depleted mice.
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