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

Abstract

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.

HCN-Channel-Dependent Hyperexcitability of the Layer V Pyramidal Neurons in IL-mPFC Contributes to Fentanyl-Induced Hyperalgesia in Male Rats

“…Usually, HCN channels have four subtypes which are predominantly expressed in pyramidal neurons of the mPFC, where they control resting membrane properties and modulate neuronal excitability [28][29][30][31][32]. HCN channels can facilitate DRG neuron excitability in neuropathic pain [33], blocking it with ZD7288 can provide analgesic effect [34][35][36][37]. On the contrary, in supraspinal central there are reports that decreased open probability of HCN causes an enhanced input resistance and neuronal excitability observed in mPFC after neuropathic pain [29,30].…”

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain

“…Hyperpolarization‐activated current ( I h ) in neurons ( I f in the heart), the current produced by hyperpolarization‐activated cyclic nucleotide‐gated (HCN) channels, was originally associated with rhythmic electrical activity (Brown et al., 1979; Bucchi et al., 2012; DiFrancesco, 1991; Hutcheon & Yarom, 2000; Nolan et al., 2003; Noma & Irisawa, 1976; Pape, 1996; Vasilyev & Barish, 2002; Yao et al., 2003). HCN channels have also been found and functionally studied in primary nociceptive pathways where they were later characterized as a ‘pain pacemakers’ and considered to be a potential molecular target for the development of new pain therapeutics (Alles & Smith, 2021; Bader & Bertrand, 1984; Balducci et al., 2021; Bernard Healey et al., 2021; Chaplan et al., 2003; Cook & Goldstein, 2021; Dini et al., 2018; Dunlop et al., 2009; Gao et al., 2012; Harper & Lawson, 1985; Lee et al., 2019; Maher et al., 2009; Mayer & Westbrook, 1983; McClure et al., 2011; Resta et al., 2018; Sartiani et al., 2017; Tsantoulas et al., 2016; Vasilyev et al., 2009; Wickenden et al., 2009). However, although HCN channel function in nociceptive neurons has been extensively studied, there is still a need for better understanding of how interactions of HCN with other ion channels control dorsal root ganglion (DRG) neuron firing.…”

HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice

“…Recently, there has been increasing attention on the involvement of HCN channels in pain [ 28 , 29 , 30 , 31 ]. Both HCN1 and HCN2 channels in the peripheral nervous system participate in nociceptive processing, thereby influencing neuropathic and inflammatory pain [ 32 , 33 ].…”