Gateways to Therapy?
The list of molecular suspects in chronic pain is chock full of ion channels. Throughout pain pathways, these proteins nestle in cell membranes and regulate the influx of positively charged ions. As a result, they hold sway over the firing of neurons, and the sensation of pain. So when researchers hunt for targets for pain therapeutics, their search often leads them to ion channels.
A popular group is the transient receptor potential (TRP) channel superfamily, and a new collection of reviews in Current Topics in Medicinal Chemistry, all published online June 14, pays homage to TRP targets (see Eid et al., 2011 for an introduction to the series). Those channels are not alone in contributing to pain, however. Here, PRF surveys three recent studies that vet additional channels as potential drug targets.
T-Type Calcium Channels: A New Role in Irritable Bowel Syndrome
Work published online June 20 in Proceedings of the National Academy of Sciences USA reveals that the T-type voltage-gated calcium channel Cav3.2 may play a pivotal role in the chronic visceral hypersensitivity of irritable bowel syndrome (IBS), and suggests that the channel may be a useful analgesic target in IBS. Researchers from France and Canada, led by Emmanuel Bourinet and Denis Ardid, found that Cav3.2 was expressed and functional in colonic dorsal root ganglion (DRG) nociceptors in rats. Intracolonic injection of sodium butyrate, to mimic the high butyrate concentrations seen in some patients with IBS, produced pain hypersensitivity, and experiments showed that butyrate upregulated T-type (transient) currents in DRG neurons. The change in T-type channel activity appears to account for pain hypersensitivity in this model, because knockdown of Cav3.2 reversed the hypersensitivity. Local and systemic administration of partially selective T-type channel blockers likewise abolished the butyrate-induced hypersensitivity.
The authors note that T-type calcium channels are already being pursued as analgesic targets for other pain conditions. Their findings indicate that IBS and possibly other types visceral pain may offer additional uses for T-type calcium channel inhibitors.
HCN Channels: Targets for Spinal and Trigeminal Neuropathic Pain
Less is known about the role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels in pain. These nonselective cation channels generate hyperpolarization-activated currents (Ih), which serve a pacemaker function in the heart and also occur in medium- and large-diameter DRG neurons. Increased activity of HCN channels in DRG neurons after injury contributes to spontaneous discharge of the neurons and mechanical allodynia, making the channels potential targets for treating neuropathic pain (Chaplan et al., 2003). A similar role has been suggested in the trigeminal sensory system of the face (Wells et al., 2007).
In a paper published online June 8 in Pain, researchers directed by Seog Bae Oh, Seoul National University, and Sung Jun Jung, Hanyang University, Seoul, Korea, provide additional evidence that HCN channels contribute to facial neuropathic pain. Their results suggest that inhibition of the HCN-characteristic Ih currents in trigeminal ganglia neurons reverses mechanical allodynia in rats following chronic constriction injury of the infraorbital nerve, a model of trigeminal neuropathic pain. The investigators achieved the inhibition of Ih currents using eugenol, a natural product that gives cloves their aroma. They propose that this compound, which is already used as a local anesthetic for tooth pain, could also be beneficial for neuropathic pain. Previously, the same group showed that eugenol can exert analgesic effects through inhibition of voltage-gated sodium and calcium channels, but their new data suggest it is at least five times more potent at inhibiting Ih currents.
Kir Channels: A Potential Target in Glial Cells
Pain-producing ion channels usually turn up in neurons, but one line of investigation focuses on a glia-specific inward rectifying potassium (Kir) channel as a possible therapeutic target. In satellite glial cells (SGCs) of sensory ganglia, these channels are thought to regulate extracellular K+ concentrations, and thus to impact the excitability of primary sensory neurons (Hanani, 2005). A study reported online June 14 in Pain, from Shigeji Matsumoto, Nippon Dental University, Tokyo, Japan, and colleagues, advances the case for Kir channels in pain.
The researchers showed that expression of one channel subunit, Kir1.4, in trigeminal ganglia SGCs decreased in a rat inflammatory pain model. Further, Kir currents (defined as those that respond to increased extracellular K+ and are blocked by Ba2+) in SGCs were reduced in the inflamed tissue. These results demonstrate that inflammation suppresses normal Kir channel activity, which the authors suggest renders neurons more excitable and leads to pain. Backing up that idea, an earlier study showed that Kir1.4 knockdown in trigeminal ganglia SGCs is sufficient to produce pain (Vit et al., 2008). If, indeed, downregulation of glial Kir channels contributes to neuropathic and inflammatory pain, then ramping up the activity of these channels could be a novel strategy for pain treatment.
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