HCN2 ion channels: basic science opens up possibilities for therapeutic intervention in neuropathic pain

Abstract

Nociception - the ability to detect painful stimuli - is an invaluable sense that warns against present or imminent damage. In patients with chronic pain, however, this warning signal persists in the absence of any genuine threat and affects all aspects of everyday life. Neuropathic pain, a form of chronic pain caused by damage to sensory nerves themselves, is dishearteningly refractory to drugs that may work in other types of pain and is a major unmet medical need begging for novel analgesics. Hyperpolarisation-activated cyclic nucleotide (HCN)-modulated ion channels are best known for their fundamental pacemaker role in the heart; here, we review data demonstrating that the HCN2 isoform acts in an analogous way as a 'pacemaker for pain', in that its activity in nociceptive neurons is critical for the maintenance of electrical activity and for the sensation of chronic pain in pathological pain states. Pharmacological block or genetic deletion of HCN2 in sensory neurons provides robust pain relief in a variety of animal models of inflammatory and neuropathic pain, without any effect on normal sensation of acute pain. We discuss the implications of these findings for our understanding of neuropathic pain pathogenesis, and we outline possible future opportunities for the development of efficacious and safe pharmacotherapies in a range of chronic pain syndromes.

Loss of HCN2 leads to delayed gastrointestinal motility and reduced energy intake in mice

“…Though homozygous HCN2-KO mice are born in Mendelian ratios from heterozygous parents, they begin to display a severe phenotype between the second and third weeks of life[ 5 , 6 ]. Most notably, HCN2-KO mice display cardiac dysrhythmias, frequent epileptiform spike-wave discharges (SWDs), ataxia, tremor, reduced sensitivity to neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth[ 5 – 8 ]. Of these numerous phenotypes, several have been characterized on the cellular level, but the severe growth defect has yet to be recapitulated with cardiac or neuron-specific Hcn2 deletion [ 5 – 8 ] [ 9 ] [ 6 , 10 ].…”

“…Most notably, HCN2-KO mice display cardiac dysrhythmias, frequent epileptiform spike-wave discharges (SWDs), ataxia, tremor, reduced sensitivity to neuropathic and inflammatory pain, antidepressant-like behavior, infertility, and severely restricted growth[ 5 – 8 ]. Of these numerous phenotypes, several have been characterized on the cellular level, but the severe growth defect has yet to be recapitulated with cardiac or neuron-specific Hcn2 deletion [ 5 – 8 ] [ 9 ] [ 6 , 10 ]. Here, we present the first detailed characterization of a spontaneous mutation in Hcn2 found in Tremor and Reduced Lifespan 2 (TRLS/2J) mice.…”

Etiology and Pharmacology of Neuropathic Pain

“…Changes in Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels. HCN channels have emerged as a promising peripheral drug target for neuropathic as well as inflammatory pain (Chaplan et al, 2003;Emery et al, 2011Emery et al, , 2012Noh et al, 2014;Young et al, 2014;Tsantoulas et al, 2016). HCN2 is expressed in about half of small somatosensory neurons, which are mainly nociceptors, and plays an important role in the control of firing frequency in response to noxious stimuli (Emery et al, 2011).…”

Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity

“…The mechanisms governing the remaining difference are not clear, but a likely explanation is that under chronic pain conditions, Kcns1 works in synergy with injury-induced plasticity, such as inhibition of other Kv channels and/or sensitization of Na v and HCN channels. 44 , 45 , 49 According to one hypothesis, hyperactivity in low-threshold Aβ mechanoreceptors due to Kcns1 dysfunction can mediate mechanical allodynia in neuropathic states due to central sensitisation maintained by C-fiber input. It has been proposed that central sensitisation may even be partly sustained by activity in Aβ fibers that have undergone injury-induced phenotypic switch in their neurochemical complement.…”

“… 10 Consequently, determining the molecular constituents of pain sensitivity, and in particular genes influencing susceptibility to chronic pain, remains an important endeavour of pain research. 4 , 44 , 45 , 49 …”