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Non-canonical Molecular Targets for Novel Analgesics: Intracellular Calcium and HCN Channels


Daniel C. Cook and Peter A. Goldstein*   Pages 1 - 15 ( 15 )


Pain is a prevalent biopsychosocial condition that poses a significant challenge to healthcare providers, contributes substantially to disability, and is a major economic burden worldwide. An overreliance on opioid analgesics, which primarily target the μ-opioid receptor, has caused devastating morbidity and mortality in the form of misuse and overdose-related death. Thus, novel analgesic medications are needed that can effectively treat pain and provide an alternative to opioids. A variety of cellular ion channels contribute to nociception, the response of the sensory nervous system to a noxious stimulus that commonly leads to pain. Ion channels involved in nociception may provide a suitable target for pharmacologic modulation to achieve pain relief. This narrative review summarizes the evidence for two ion channels that merit consideration as targets for non-opioid pain medications: ryanodine receptors (RyRs), which are intracellular calcium channels, and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which belong the superfamily of voltage-gated K+ channels. The role of these channels in nociception and neuropathic pain is discussed and suitability as targets for novel analgesics and antihyperalgesics is considered.


Neuropathic pain, drug development, HCN, ryanodine receptor, analgesic, antihyperalgesic


Department of Anesthesiology, Weill Cornell Medicine, New York, Department of Anesthesiology, Weill Cornell Medicine, New York

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