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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Sensory dysfunction, including chronic pain and itch, is often associated with peripheral sensitization of sensory neurons, with communication between nerve and local tissue environment emerging as an important contributor in regulating the response in many pathologies. Pro-inflammatory mediators released by local stromal and immune cells can modulate ion channels and thus sensory neuronal excitability, and we sought to investigate this using techniques including multi-electrode array and neuropeptide release assays. The hematopoietic growth factor and cytokine GM-CSF was of particular interest due to robust analgesia observed in early anti-GM-CSF clinical studies in osteoarthritis. In order to understand the mechanism by which GM-CSF could alter neuronal signalling in pain pathways associated with chronic neuropathic pain, we deployed a variety of electrophysiological, immunological, transcriptomic and behavioural techniques in wild-type and transgenic animals targeting the GM-CSF pathway. We show GM-CSF does not directly alter sensory neuronal excitability, but we identify a novel and fundamental process whereby peripheral nerve injury induces GM-CSF release from group 2 innate lymphoid cells (ILC2s) and instructs vertebral bone marrow emergency myelopoiesis. As such, we link meningeal immunity to vertebral bone marrow emergency myelopoiesis in neuropathic pain and reveal the mechanism by which GM-CSF acts to orchestrate this neuroimmune axis.
Note all experimental procedures were carried out in accordance with UK Home Office Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals.
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