Opioids are decreasing symptoms of the pain rather than the underlying mechanism. In addition, these drugs damage the reward pathway in the brain and can lead to addiction. Fortunately, opioids are not the only pharmaceutical option for pain management: non-addictive pain relievers are widely available over the counter and by prescription. But research shows that prescription pain relievers, whether opiate-based or not, work well enough for only about 70% of patients. We need better opportunities.
Humans’ relationship with opioids is ancient. It began 8000 years ago when people started using opioids as medicine in a less potent but still abusive form. The opiate use problems crescendo in recent decades as broader indications and higher doses of these drugs have led to today’s epidemic that has affected countless lives.
Spurred on by the opioid epidemic, scientists today are diving deeper into the neurobiological mechanisms of pain. They aim to find new drug targets to effectively treat pain without causing addiction. This new generation of drugs can bypass the dopamine and opioid pathways entirely by directly targeting the nociceptor pathway — a network of neurons throughout the body responsible for mediating pain signaling. By carefully examining these drug candidates in humans, animals and IVF model systems, researchers hope to develop a more targeted class of pain relievers that may help reduce dependence on addictive substances.
The relationship between pain and addiction
At the physiological level, chronic pain and addiction result from complementary neural feedback loops fed by the opioid and dopamine systems. First, chronic pain can develop after repeated stress, inflammation, or acute injury, while addiction results from repeated exposure to an addictive substance. Both induce epigenetic changes in gene expression and protein localization in neurons. But while chronic pain mainly involves changes in pain sensation circuits, causes of addiction additional changes in reward center of the brain. Opioids work by dulling the sensation of pain in the brain, but they also act unnecessarily on the reward pathway, making them addictive. Therefore, analgesics that affect pain signaling at the pain site and do not affect the reward pathway would offer therapeutic benefit without causing additional harm.
Techniques used to study chronic pain
Scientists have used a variety of approaches to investigate the effects of new painkiller drug candidates on nociceptor signaling. Standard methods include structural modeling of receptors and ligands, behavioral assessment, functional magnetic resonance imaging (fMRI), and electrophysiology. Together, these methods assess whether the drug has an appropriate effect on brain activity and reduces pain.
Electrophysiology plays a critical role in the screening of therapeutic candidates. This technique allows researchers to study how compounds affect the electrical activity of neurons and neural circuits. For these experiments, the researchers grew dorsal root ganglion neurons and used inflammatory compounds to cause the neurons to fire as if signaling inflammatory pain. The researchers then treated the neurons with pain-relieving drug candidates and watched them for a reduction in neuronal activity.
However, conventional electrophysiological methods, such as patch-clamp, have low throughput, making it challenging to efficiently discover and test new drug candidates. For this labor-intensive method, a highly trained scientist uses a micropipette to manipulate an individual cell and measure its electrochemical activity. Data collection is also limited because researchers can only study each neuron for about an hour before the cell dies. Similarly, fMRI and behavioral studies return other types of high-quality data, but also at a slow pace. More recently, however, scientists are accelerating therapeutic discoveries with a new type of analysis using bioelectronic assays.
In bioelectronic assays, live neurons are grown in a multiwell plate containing multielectrode arrays (MEAs) at the bottom of each well that continuously record cell activity. Instead of measuring a single cell, these noninvasive bioelectronic assays can measure activity over time in an entire neural network. Researchers can conduct bioelectronic analyzes of generic cell lines or cell lines obtained from a specific patient. Bioelectronic analysis of patient-specific patterns of chronic pain has helped accelerate the discovery of new pain relievers.
Targeted search to find new pain relievers
To develop a non-addictive pain reliever, scientists looked for proteins that appear on pain neurons but not in the reward pathway, no small task. However, researchers have identified specific genes that fit the bill by studying rare genetic diseases associated with pain.
The sodium channels, Nav1.7, Nav1.8, and Nav1.9, have a critical role in pain perception, and early work revealed the genes encoding these proteins. (Hakobyan, Rose, Yang, Cummins, Fiel, tree). These channels are optimal pain targets because they are only found in the dorsal root ganglion. Ideally, compounds that target these channels will do so dull pain without causing addiction. IN remarkable studyscientists characterize the painful condition known as “burning man syndrome” or Hereditary erythromelalgia (IEM), which is caused by a mutation in the Nav1.7 gene. This study is one of the first studies in humans confirming that gain-of-function mutations in these genes cause disorders associated with increased pain. Conversely, the researchers found that the loss-of-function mutations made the individual less able to feel pain.16 Armed with this knowledge, the researchers could finally conduct targeted studies to search for a new class of pain relievers.
An early pharmacological breakthrough came from the Waxman lab in 2012.17,18 Waxman’s team studied two patients with IEM, and structural modeling of the mutated S241T Nav1.7 channel predicted that these individuals would respond to the antiepileptic drug carbamazepine. fMRI assessments revealed that carbamazepine treatment reduced brain activity associated with pain signaling in both patients. In addition, both patients reported a significant reduction in pain: In one patient, carbamazepine treatment halved the time spent in pain per day, with fewer cases of awakening from pain at night. The other patient reported that the drug reduced pain time by about 85 percent. Bioelectronic analysis confirmed this positive effect at the cellular level: Waxman’s group cultured dorsal root ganglion neurons expressing the same Nav1.7 sodium channel mutation of the patients and exposed them to heat, a stimulus that causes pain in individuals with IEM. Heat exposure increased neuronal activation, and carbamazepine treatment reduced heat-induced activity, reflecting its clinical effects.
Since then, researchers have advanced a dozen new compounds that selectively block Nav1.7 and Nav1.8 sodium channels and one that blocks Nav1.9 for clinical trials, with three in Phase 3. These researchers aim to identify treatments for conditions ranging from IEM to diabetes neuropathy. In general, these compounds do not appear to be addictive and do not cause dangerous side effects; however, they show varying efficacy in reducing pain. Therefore, the search continues to uncover potential new inhibitors of Nav1.7 and Nav1.8 as small molecules and therapeutic antibodies. Some researchers they have designed high performance screens based on bioelectronic assays to accommodate demand. Although these screening systems are still in their infancy, once operational, they promise to greatly accelerate the identification of promising, physiologically relevant analgesic candidates.
The research group looking for a better class of pain relievers is relatively young, but it’s making rapid progress. Regardless of which method uncovers new pain-relieving targets, researchers must evaluate these new compounds for addictive properties and unexpected side effects. These efforts will lead to pain relievers that work through a more efficient, targeted mechanism. Over time, people may have access to a more diverse selection of non-addictive pain relievers, and doctors will be able to assign patients treatment based on their unique physiological makeup. Overall, this promising area of research will improve the way we treat pain and reduce the number of people who rely on opioids. As scientists strive to differentiate pain from addiction, the future of pain treatment is increasingly bright.
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