Finding non-opioid ways to provide analgesia, or pain relief, is a key focus on medical research. While opioids are powerful and currently still necessary in many situations, they also have a high risk of dependence and misuse. One potential alternative to the analgesic pathway used by opioids that is being explored is pain relief through the α2A-adrenergic receptor. 

Opioids are a class of pain-relieving drugs that function by interacting with opioid receptors found in cells in the central nervous system. They can bring much-needed relief to patients experiencing pain from disease or a surgical operation but carry a risk of addiction because they can induce euphoria that becomes harder and harder to satisfy as a person builds a tolerance towards opioids. Such a reliance on opioids is known as opioid-use disorder, a condition 3 million Americans and 16 million people worldwide suffer from.¹ Prolonged opioid use, because the drugs depress heartbeat and breathing, can be fatal; in 2021, there were over 80,000 opioid-involved overdose deaths in the United States.² 

Because of the prevalence and dangers of opioid-use disorder, there is great interest in identifying and developing non-opioid pain-relief drugs. A study published in September 2022 from an international collaboration of scientists is a promising step in this direction.³ They elected to focus on agonists, or binding partners that initiate a physiological response, for the α2A-adrenergic receptor (α_2AAR), a non-opioid receptor that is known to be related to pain relief. Several drugs that bind to this receptor are currently used in hospital settings, but are unavailable for broader use because they have sedative properties and cannot be taken orally. The research team thus sought to identify molecules that could induce pain relief without these downsides. 

They first screened 300 million molecules for their ability to interact with α2A-adrenergic receptor, but in a mechanism distinct from the ones used by the currently known agonists, to find candidates for pain relief therapeutics. By computationally simulating how the molecules might physically interact with the receptor, they identified 48 target molecules that were then synthesized and analyzed in the lab. This enabled the researchers to uncover the precise mechanisms by which the molecules bind to α_2AAR. For example, whereas the previously described agonists overwhelmingly use an imidazole group (a ring of carbon, nitrogen, and hydrogen atoms) to bind to α_2AAR, the newly identified binding partners used a more diverse range of chemical functional groups, suggesting that synthetic molecules with novel chemical structures could prove effective at relieving pain via binding to α_2AAR. 

The researchers then investigated pain-relieving properties of these agonists by administering them to mice with a nerve injury. An important prerequisite for an anesthetic drug is that it has good permeability – the ability to permeate through cell membranes and reach their receptors. Because the synthesized agonists were small in size and not highly charged, they were able to easily permeate into the brain and cerebrospinal fluid. As a control, some mice were administered dexmedetomidine, a commonly used drug targeting α_2AAR. The two classes of drugs desensitized the mice to several different types of pain to a similar extent, though the synthetic agonists did not affect the mice’s balance or coordination like dexmedetomidine did. Additionally, the most promising synthetic agonist, which the researchers called ‘9087, did not induce any side effects related to weight gain or hyperglycemia, which can occur with traditional α_2AAR agonists. 

Though more research and clinical trials are needed before these drugs can be administered to humans, the study introduced potential new non-opioid pain relief agents that act on the α2A-adrenergic receptor. It may ultimately serve as an important milestone in the development of more tolerable and accessible medicine for those in pain.  

References 

1. Azadfard, M., Huecker, M. R. & Leaming, J. M. Opioid Addiction. in StatPearls (StatPearls Publishing, 2023). 

2. Drug Overdose Death Rates. National Institute on Drug Abuse https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates (2023). 

3. Fink, E. A. et al. Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor. Science 377, eabn7065 (2022), DOI: 10.1126/science.abn7065