A pharmacological approach to define the contribution of Nav1.7 to pain pathways (2016–2018)

Abstract:
Chronic pain is a debilitating condition affecting one in five Australians. The annual health expenditure on persistent pain, estimated at $34 billion in 2007, exceeds that of cancer, diabetes, and stroke. Chronic pain remains difficult to treat because existing analgesics suffer from limited efficacy and are associated with serious adverse effects. Nav1.7 is one of nine isoforms of the mammalian voltage-gated sodium channel and has received considerable attention as a putative analgesic target based on human loss-of-function mutations that result in Congenital Insensitivity to Pain. Despite the unparalleled promise of Nav1.7 as a pain target, it has been difficult to recapitulate the pain-free phenotype using pharmacological tools as lack of selectivity at related NaV isoforms is associated with debilitating and potentially fatal side effects. Thus, it remains unclear whether Nav1.7-selective inhibitors are able to deliver on the promise of a universally effective analgesic. Specifically, it remains to be seen whether it is possible to achieve a graded analgesic response that eliminates pathological pain while maintaining normal nociceptive function, which is essential for survival and to avoid inadvertent self-harm. In addition, while inhibition of Nav1.7 at any level of the pain pathway ¿¿¿ from peripheral sensory nerve endings to the spinal projections of these neurons ¿¿¿ should mediate analgesia, it is unclear which of these strategies will be most beneficial clinically, or which painful conditions would be most amenable to treatment with NaV1.7 inhibitors. We recently discovered Pnc1a, the most Nav1.7-selective peptide reported to date and thus have a unique opportunity to elucidate the role of NaV1.7 in pain pathways. We will assess the effect of Pnc1 on neuronal excitability and pain phenotypes in clinically relevant pain models, and will optimize the pharmacophore of Pnc1a with the aim to develop novel analgesics.
Grant type:
NHMRC Project Grant
Researchers:
  • Principal Research Fellow
    Institute for Molecular Bioscience
    Affiliate Senior Research Fellow
    School of Pharmacy
    Faculty of Health and Behavioural Sciences
  • Principal Research Fellow
    Centre for Advanced Imaging
    Affiliated Senior Lecturer
    School of Chemistry and Molecular Biosciences
    Faculty of Science
    Affiliate Research Fellow
    Institute for Molecular Bioscience
Funded by:
National Health and Medical Research Council