New "Pathway" Provides Mute Button to Curb Chronic Pain
Chronic pain affects around 100 million adults in the United States, topping the incidence of diabetes, heart disease, and cancer combined.1 But doctors are still on the look out for a treatment that can curb pain symptoms without putting patients at risk for addiction and other harmful side effects.
Adenosine, a purine nucleoside, may be the key doctors are looking for —a "mute button" to neuropathic pain. It could help many kinds of chronic pain sufferers, especially cancer patients, providing a safe adjuvant that takes the emphasis off analgesics.
While doctors have been aware of adenosine's connection to pain for quite some time, clinical tests have run into issues with cardiovascular side effects.2,3 Much research focused on A1AR/A2AAR agonists, which correspond to 2 of the 4 receptor subtypes found in vertebrates.4
However, a new study in Brain has found evidence of another adenosine pathway devoid of complications.5 A new way to treat chronic pain may be on the horizon.
Preliminary Study Results
By testing a population of rats and mice, researchers looked at one of the less-explored receptors: A3AR, now known as ADORA3. Testing chronic pain models, like chemotherapy-induced peripheral neuropathy, researchers found evidence that adenosine may not just be neuroprotective and anti-inflammatory,6-9 but anti-nociceptive, as well.
Using ABT-702 – an inhibitor – researchers reduced the activity of the adenosine kinase enzyme, which increased the likelihood of extracellular adenosine concentration and signaling.3
Subsequently, the animals had a reversal in their sensitivity to stimuli at the peak pain levels of Chronic Constriction Injury (CCI). Afterwards, researchers attenuated these effects with an antagonist called MRS1523.
CCI isn't the only etiology of neuropathic pain, obviously. Cancer patients who are treated with chemotherapy, like paclitaxel, may suffer from peripheral neuropathy,10,11 which forces them to limit or reduce their treatments. Interestingly, ABT-702 also reversed chemotherapy-induced allodynia and hyperalgesia pain at the peak of symptoms, and MRS1523 attenuated the blockage of pain signals.
May Help Chemo-Induced Neuropathy
According to lead author of the research Daniela Salvemini, PhD, a professor at the Saint Louis University School of Medicine in Missouri, these results show that using the ADORA3 pathway could be useful for chemotherapy patients.
ADORA3 "could be given as an adjunct to chemotherapeutic agents to prevent the pain from happening" Dr. Salvemini said, "or we can give the agent in patients that already have the pain from the chemotherapeutic agent and potentially ameliorate the pain response, reverse it that is."
They found further hope in an ADORA3 agonist called MRS5698. It reversed peak allodynia in rats with CCI in a rapid, dose-dependent manner that mirrored morphine, providing results in less than 30 minutes.
In just 1 hour, allodynia from spared nerve injury and spinal nerve ligation reduced by a mean of 82% and 98%, respectively. Even in a more complex pain model, like cancer-induced bone pain, its efficacy remained.
"As A3AR agonists are in clinical trials as anticancer agents,7 the potential dual pharmacological properties (anticancer effects and pain-relieving properties) of an A3AR agonist may offer a significant therapeutic advantage," wrote Dr. Salvemini and colleagues.
According to the research, MRS5698 didn't show any loss of efficacy over time, change in nociception functioning, or development of tolerance, and without an inherent reward, the drug seemed to avoid having any abuse potential. It also showed independence from other endogenous pathways because various opioid and cannabinoid antagonists had no bearing on its effects.
This means ADORA3 signaling could be combined into a safe and effective multi-modal approach for treating chronic pain. Patients could then rely less on opioids while still having proper management of their pain, Dr. Salvemini said.
As for the underlying mechanisms behind ADORA3's connection to anti-nociception, the answers lay in the central nervous system (CNS), where Dr. Salvemini and colleagues were able to find ADORA3 mRNA transcripts and proteins. By using a control gene found in the same tissues, they performed tests that showed ADORA3's anti-nociception.
After reducing neuronal responses in the highest thermal and mechanical stimuli, further data showed ADORA3 was being activated in the brain's rostral ventromedial medulla (RVM), suppressing spinal nociception through bulbospinal inhibitory circuits, which are nerve fibers that connect the medulla oblongata to the spinal cord.
"We are planning to carry out the necessary work to advance highly selective A3AR agonists to clinical trials for neuropathic pain as novel non narcotic analgesics while continuing to explore molecular mechanisms engaged by A3AR agonisms," Dr. Salvemini said.
This research was funded through grants and other forms of support from the National Cancer Institute, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Foreign Investment Review Board, and Saint Louis Cancer Center. The authors reported no conflicts of interest.