HCN2 channels account for mechanical (but not heat) hyperalgesia during long-standing inflammation

Abstract

There is emerging evidence that hyperpolarization-activated cation (HCN) channels are involved in the development of pathological pain, including allodynia and hyperalgesia. Mice lacking the HCN isoform 2 display reduced heat but unchanged mechanical pain behavior, as recently shown in preclinical models of acute inflammatory pain. However, the impact of HCN2 to chronic pain conditions is less clear and has not been examined so far. In this report, we study the role of HCN2 in the complete Freund's adjuvant inflammation model reflecting chronic pain conditions. We used sensory neuron-specific as well as inducible global HCN2 mutants analyzing pain behavior in persistent inflammation and complemented this by region-specific administration of an HCN channel blocker. Our results demonstrate that the absence of HCN2 in primary sensory neurons reduces tactile hypersensitivity in chronic inflammatory conditions but leaves heat hypersensitivity unaffected. This result is in remarkable contrast to the recently described role of HCN2 in acute inflammatory conditions. We show that chronic inflammation results in an increased expression of HCN2 and causes sensitization in peripheral and spinal terminals of the pain transduction pathway. The contribution of HCN2 to peripheral sensitization mechanisms was further supported by single-fiber recordings from isolated skin-nerve preparations and by conduction velocity measurements of saphenous nerve preparations. Global HCN2 mutants revealed that heat hypersensitivity-unaffected in peripheral HCN2 mutants-was diminished by the additional disruption of central HCN2 channels, suggesting that thermal hyperalgesia under chronic inflammatory conditions is mediated by HCN2 channels beyond primary sensory afferents.

Contribution of hyperpolarization-activated channels to heat hypersensitivity and ongoing activity in the neuritis model

“…However, contrary to this previous report, a more recent paper suggests that this subtype is not responsible for inflammation-induced heat hypersensitivity (Schnorr et al, 2014). Based on these findings, it seems likely that the reversal of heat hypersensitivity by ZD7288 in the neuritis model is due to blockade of multiple channels, which may also include other HCN subtypes.…”

“…Following CCI, there is a decrease in the expression of HCN2 within the DRG and a redistribution of the channel proximal to the injury site (Jiang et al, 2008). Consistent with a role for this isoform in neuropathic pain mechanisms, deletion of HCN2 from nociceptive neurons has been shown to prevent the development of pain behaviors in the CCI model and following inflammation of the hind paw (Emery et al, 2011;Schnorr et al, 2014).…”

Increased expression of HCN2 channel protein in L4 dorsal root ganglion neurons following axotomy of L5- and inflammation of L4-spinal nerves in rats

“…Of the four isoforms of the HCN channels (HCN1-4), HCN2 is believed to play a pivotal role in chronic pain on the basis that: (a) deletion of HCN2 in nociceptive neurons prevented the development of pain behaviors in the CCI model and inflammatory pain models (Emery et al, 2011;Schnorr et al, 2014, see also Emery et al, 2012 for review) and (b) HCN2 expression was increased in small DRG neurons following chronic hindlimb inflammation (Weng et al, 2012).…”

“…Since most of the proteins that are expressed in the somata of primary afferent (DRG) neurons are also expressed in their free nerve endings and in their central and peripheral axonal branches (see Basbaum et al, 2009), it is possible that changes in HCN expression in the somata of DRG neurons may also occur in their peripheral terminals. Changes in expression and/or function of HCN channels at peripheral nerve terminals may result in a lowered threshold and/or a greater gain of the stimulus-response relationship (Schnorr et al, 2014) and may also contribute to SA generation and thereby to PNP.…”

The Inhibitory Effects of Ketamine on Human Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels and Action Potential in Rabbit Sinoatrial Node

“…Studies have shown that HCN2 channels play a central role in inflammatory and neuropathic pain [43,44,45]. Zhou et al [46] indicated that HCN channels may contribute to regional anesthetic effects of lidocaine.…”