The search for novel non-opioid analgesics.

Channeling Relief: The role of ion channels in pain

Pain is an unpleasant physical sensation caused by injury or inflammation in sensory nerves and surrounding tissues, increasing action potential firing in hypersensitized neurons which pass these signals to the spinal cord and up to pain processing centers in the brain. Its goal is to prevent further injury and protect our body’s well-being. However, chronic pain, affecting up to 40% of the human population, is a condition where pain persists even when the underlying cause is no longer present. This can become debilitating and is currently not well managed by available medications. Ion channels have been implicated in pain pathways and are major therapeutic targets for chronic pain treatment. By more specific targeting of certain ion channels, drugs may become safer, with fewer side effects and lower addiction risk.

Ion channels as pain targets

Pain as a channelopathy

Human sensory pathways inform us about our environment. Ion channels localized in primary sensory neurons and other relevant neuronal structures are involved in pain processing. Among these channels, sodium (eg. NaV1.7 and NaV1.8), calcium, transient receptor potential (TRP), and PIEZO and purinergic P2X3 channels have been flagged as great potential drug targets to combat chronic pain. In 2021, the Nobel Prize was awarded for deciphering the ion channel-mediated mechanisms for how the nervous system senses pressure and temperature. Interestingly, both of identified channels have also been implicated in allodynia (Piezo2) and analgesia in chronic neuropathic pain (TRPV1).

Alleviating pain

Among currently approved drugs, almost 20% of drugs targeting human receptors, target ion channels. Nevertheless, pain drug targets go in and out of fashion, and mostly so due to poor clinical results. TRPV1 and TRPA1 modulators and CaV2.2 channels are slowly being forgotten, however, work on NaV1.7 and NaV1.8 channels continues due to human genetic channelopathies and promising clinical success. KV7.x channel and a9a10 nAChRs modulators are also being developed, alongside P2X receptors activated by inflammation. NMDA GluR and GABAA ligand-gated receptors are still relevant CNS drug targets.

Importantly, pharmacological benchmarking gives confidence that hits identified in screening campaigns are genuine and allows a comparison of the effects of new compounds with the literature. High throughput patch clamp screening platforms, such as the SyncroPatch 384 also allow for gene family selectivity screening of hit and lead compounds on a single plate. Imagine testing six different NaV1.x cell lines with the same state-dependent voltage protocol allowing for the potency and selectivity of each compound to be determined quickly and under similar conditions. Screens like these are very much possible, and routinely taking place in research facilities today.

The figure shows raw traces of current responses to increasing voltage steps from -60 to +60 mV (A) from an exemplar CHO cell expressing hNaV1.8 recorded on the SyncroPatch 384PE (predecessor of SyncroPatch 384; A).  Current-voltage plot (B) shows the mean of peak amplitudes normalized to the maximum of each cell ± S.E.M. for an average of 380 cells. We used a double voltage step protocol for the pharmacology experiments, and screenshot (C) of the data acquisition software shows the time course of current amplitudes after applying the two-step pulse protocol.

Tools for studying

pain-related ion channels


Pain ion channel screening

As pain-related ion channels utilize a wide variety of activation and stimulation mechanisms, identifying and screening for those ion channels as drug targets demands high flexibility and precision. When identifying drugs of choice, speed, throughput, and easy-to-use software protocols are paramount. Our automated patch clamp (APC) systems can accurately measure and analyze activation, inactivation, IC50 / EC50 parameters, and important metrics in the drug discovery of new pain-related ion channel modulators.

High-quality, high-resolution recordings of the complex biophysics of voltage-gated pain channels (e.g. NaV1.7, NaV1.8, KV7.x, and HCN2), are possible by employing excellent voltage control and seal quality. Ligand-gated receptor responses (e.g. TRPV1, TRPA1, ASIC1a) can be reliably measured using flexible liquid application techniques. Implementation in translational studies of pain-related ion channels and receptors in human iPSC-derived sensory neurons helps bridge the gap from in vitro screening to preclinical studies and clinical development of novel pain drugs, ultimately improving millions of lives around the planet.



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