Pain

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. Na_V1.7 and Na_V1.8), 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).

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 Ca_V2.2 channels are slowly being forgotten, however, work on Na_V1.7 and Na_V1.8 channels continues due to human genetic channelopathies and promising clinical success. K_V7.x channel and a9a10 nAChRs modulators are also being developed, alongside P2X receptors activated by inflammation. NMDA GluR and GABA_A 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 Na_V1.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.

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. Na_V1.7, Na_V1.8, K_V7.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.