Targeting Ion Channel Trafficking Mechanisms for Novel Analgesics

In February of this year, the New York Times reported on the increasing number of brazen robberies occurring at pharmacies throughout the USA. One thief in Rockland (ME, USA) brandished a machete and leapt over the pharmacy counter to grab oxycodone. He gulped down some of it even before he fled. In Florida, thousands of doses of oxycodone pills are dispensed in pain clinics, resulting in some calling the highway that leads into Florida, I-75, the ‘Oxy Express‘. In 2008, Ohio pharmacists dispensed 4.8 million prescriptions for hydrocodone medications, one for every 2.5 people in the state [101]. Although we have been treating pain effectively for millennia, the need for efficacious, safe but especially nonaddictive analgesics remains strong. We require analgesics that can specifically act on peripheral pain-sensing neurons and not centrally to avert addiction. In this article, I argue that the future of pain research must include the development of compounds that directly target the ion channel trafficking machinery of nociceptors.

Analgesics act by reducing the firing properties of neurons within the pain pathway. For treatment of mild pain, nonsteroidal antiflammatory drugs (NSAIDs) are recommended. These agents reduce algogenic substances, such as prostaglandins, which directly affect the firing properties of nociceptive neurons. NSAID use is widespread; however, gastrointestinal and renal toxicities associated with these agents are prevalent, with an estimated 10–20% of NSAID patients experiencing dyspepsia [1]. The development of cyclooxygenase-2 selective inhibitors, which minimize gastrointestinal effects, seemed promising, but their severe cardiovascular toxicities have dramatically restricted their use. Vioxx^®, the most famous of the cyclooxygenase-2 inhibitor drug class, had to be removed from the market owing to its toxic effects. For moderate-to-severe pain, moderate opioid agonists, such as hydrocodone, strong opioid agonists, such as oxycodone, or even morphine are used. These agents act on opioid receptors in the CNS, especially on descending pathways originating from the periaqueductal gray matter, to block pain transmission in the dorsal horn of the spinal cord. They can also act presynaptically by inhibiting neurotransmitter release from the central terminations of nociceptors in the spinal cord. Opioids do so via µ-receptors, ultimately affecting potassium and calcium conductances. As opioids act centrally, they also produce sedation, euphoria or dysphoria, nausea and vomiting, and in overdose, deadly respiratory depression.

Nonsteroidal antiflammatory drugs and opiods are very good for relieving inflammatory pain states: pain that arises from acute tissue injury or trauma. However, there are limitations to these drugs when pain results from nerve injury. Nerve injury pain, called neuropathic pain, can be caused by nerve compression, spinal cord injury, diabetes, alcoholism, cancer chemotherapy and postherpectic neuralgia. Nerve damage results in the persistent action potential firing of primary nociceptive afferents. The continual input from discharging nociceptors induces synaptic changes in the spinal cord, causing central sensitization. It is important to realize that continual discharging afferents are required for maintenance of central sensitization [2]. Therefore, for neuropathic pain, alternative types of analgesics are required. Antiepileptic drugs such as carbamazepine, phenytoin and valproate are used. These drugs directly target ion channels, particularly sodium channels, to reduce excitability. However, they are antiepileptic drugs acting centrally and, as such, are also associated with many side effects.

Are there any similarities between chronic inflammatory pain and neuropathic pain? Both pain states depend on nociceptor hyperexcitability [3–5]. Therefore, developing drugs that act peripherally, targeting ion channels and thereby reducing primary afferent sensitization, is a logical analgesic approach to take to minimize side effects and prevent addiction.

Which ion channel(s) should we target? The answer to this question is not so simple. There has been extensive research trying to determine the principle ion channels that are responsible for nociceptor hyperexcitability in animal models of inflammatory and neuropathic pain. Heavy emphasis has been placed on the central role of voltage-dependent sodium channels in primary afferent hyperexcitability. However, recent transgenic animal studies indicate that increased sodium channel activity may not be essential in the pathophysiology of inflammatory and neuropathic pain [6]. Calcium channels, in particular T-type calcium channels, have drawn considerable attention because they are upregulated in neuropathic pain [7], and specific T-type calcium channel antagonists have been tested for their abilities to treat neuropathic pain [8]. However, targeting sodium and calcium channels poses toxicity issues, because many of the same channel subtypes expressed in nociceptors are also expressed in other neuronal and non-neuronal tissues. Potassium channels also offer unique analgesic targets. Potassium currents in nociceptors are also affected by inflammation and neuropathy, and therefore developing potassium channel openers to increase their activity will impact nociceptor hyperexcitability. Potassium channels are far more diverse than sodium and calcium channels, and the unique repertoire of potassium channels that are expressed in nociceptors could be of considerable pharmacological interest [9].

From my 11 years of experience studying sodium-activated potassium (K_Na) channels, I have found their expression in rats to be the highest in trigeminal and dorsal root ganglion neurons [10,11]. Why sensory neurons express high levels of K_Na channels still remains to be fully answered. However, my research team has recently demonstrated that PKA activation results in the internalization of K_Na channels from the dorsal root ganglia neuronal membrane and this was associated with hyperexcitability [12]. The most remarkable aspect of these findings is that there is a robust ion channel trafficking capacity in nociceptive neurons: signal activation causes ion channels to move in and out of the nociceptor membrane [12–15]. Ion channel trafficking offers nociceptive neurons a rapid but prolonged method for changing their firing properties. Up until this point, many have assumed that inflammatory mediators modulate nociceptors primarily through phosphorylation-/dephosphorylation-dependent changes in ion channel gating. While this process is important, I would like to highlight that phosphorylation-dependent changes in channel gating are transient. Dorsal root ganglia neuronal hyperexcitability in either neuropathic pain or inflammatory pain occurs in the magnitude of hours, days, weeks or even years. We need to appreciate the long-term regulation of ion channels at the plasma membrane in pain-sensing neurons. This is akin to the understanding of ion channel clustering and trafficking during synaptic plasticity in the CNS. It is within the context of ion channel trafficking that I think efficacious, nontoxic analgesics can be developed. Merely applying channel blockers or channel openers will inevitably lead to adverse side effects. If we can disrupt channel trafficking mechanisms that result from prostaglandin-induced inflammatory signaling for example, we could produce an analgesic-specific effect without the side effects, such as addiction, of current analgesics. Indeed, this may be how the well-tolerated drug gabapentin, which controls the trafficking of calcium channels [16], is efficacious for neuropathic pain.

Future research is still required to understand nociceptor hyperexcitability during inflammatory and neuropathic pain signaling; we need to identify the dynamic ion channel processes associated with hyperexcitability. If we can elucidate the molecular underpinnings of nociceptor hyperexcitability, it will lead to better and safer analgesics. Unfortunately, within the USA, the NIH devotes only a fraction of a percentage of its total budget to pain research and, given the recent decline in interest for developing new therapeutics by pharmaceutical companies, it is unclear where the impetus will come for the development of novel channel targeted drugs. Perhaps the Drug Enforcement Agency, with its billion-dollar budget, could devote a portion of its resources to fund research whose sole purpose is to develop nonaddictive analgesics. It may be as cost effective as trying to protect pharmacies from bandits gallivanting down the Oxy Express.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.