Failed Osteoarthritis Drug May Mitigate Neuropathic Pain and Reduce Dependence

Andrea Hohmann, PhD, ScM, BSc

A drug that failed phase 2 studies for osteopathic pain may be granted new life as a way to treat neuropathic pain while leading to less tolerance and fewer withdrawal effects than opioids.

The drug, LY2828360, a cannabinoid type 2 (CB2) receptor agonist, was developed by Eli Lilly, and while it was not shown to decrease knee pain in osteopathic patients, it has already been deemed safe for use in humans.

“The fact that LY2828360 had already been shown to be safe in people was very exciting to us because if it was effective in blocking pain for a different, new indication (i.e. neuropathic pain due to chemotherapy treatment), it would mean that it would make the prospects of rapid translation to evaluation in the clinic possible,” Andrea Hohmann, PhD, ScM, BSc, a professor in the Indiana University Bloomington College of Arts and Sciences' Department of Psychological and Brain Sciences, and lead author of the study, told MD Magazine.

First, the researchers used a chemotherapy drug, paclitaxel, to induce neuropathic pain in male mice. They tested these mice and confirmed that they had hypersensitive responses to cold and mechanical stimulation, implying that they had developed neuropathic pain from the drug. Next, they gave the mice morphine. As expected, these mice developed a tolerance to the drug, as well as a physical dependence. The researchers measured this physical dependence by observing the withdrawal symptoms after giving the mice naloxone, an opioid blocker.

The team used LY2828360 in 2 experimental groups—in the first, they gave the mice a little bit of LY2828360 with each dose of morphine. In the second, they treated the mice for 2 weeks with LY2828360 first, and then switched to morphine. In both groups, the experimental drug seemed to prevent tolerance and reduce the signs of withdrawal. The higher dose of LY2828360 provided pain relief to the mice, even during the 2 weeks when they did not receive any morphine.

“Our studies suggest that the CB2 agonist was effective in treating established neuropathic pain in mice,” Hohmann said. “The target is very promising because activation of this receptor unlikely to be associated with psychoactivity, physical dependence or addiction.”

Along with testing the efficacy of the drug in humans with neuropathic pain, the team is also planning more studies to better understand the drug’s mechanism of action. They will use mice with the CB2 receptor knocked out in specific tissues, to understand how the drug exerts its effects, and whether or not it might be useful for other types of pain.

“Unlike CB1 receptors, which are found at high levels in the brain, CB2 receptors are mostly expressed in immune cells and are largely absent from the brain,” Hohmann said. “We still need to better understand the cell types that contain CB2 receptors that are responsible for both the analgesic effects of LY2828360 and the ability of this compound to reduce opioid tolerance and physical dependence.”

The study, “Slowly Signaling G Protein—Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence,” was published in the Journal of Molecular Pharmacology.