Non-opioid treatment for chronic pain using a neurotensin receptor 1 modulator

Unmet Need

For individuals experiencing chronic pain, day-to-day tasks and activities can become difficult or impossible. It can also lead to other long-term health challenges including insomnia, stress, anxiety, and depression. Chronic pain is so pervasive, it is thought to affect approximately 25% of adults in the U.S. and accounts for over 20% of all doctor visits. Treatment of chronic pain is limited to light relief, such as is found in over-the-counter topical ointments, nonsteroidal anti-inflammatory drugs, and muscle relaxers, to stronger drugs such as medical marijuana and opioids. Although effective in relieving pain, opioids have become a tremendous public health crisis due to their addictive properties and diminishing effectiveness with prolonged use. There is a need for non-addictive pain treatments that substantially reduce discomforts and improve the quality of life in patients who suffer from chronic pain.

Technology

Duke inventors have developed a small molecule, SBI-553, that alleviates chronic pain-associated behaviors in mice without being addictive. This molecule is intended to be used in situations of debilitating chronic pain when opioids are often prescribed, such as with former military personnel who have experienced combat-related trauma and musculoskeletal injuries. Specifically, researchers have harnessed neurotensin receptor 1’s (NTSR1) ability to alleviate pain while selectively blocking the side effects through a beta-arrestin-biased NTSR1 modulator (SBI-553). Neurotensin receptors are found in pain circuits of the central nervous system and have long been investigated for their pain alleviation potential. Typical activation of NTSR1 results in adverse side effects such as hypotension, hyperthermia, motor impairment and other life-threatening conditions. Now, with the beta-arrestin-biased NTSR1 ligand (SBI-553), the analgesic effects of NTSR1 can be activated, while eliminating these usual negative side effects. This has been demonstrated in male mice experiencing neuropathic chronic pain induced by paclitaxel, a chemotherapy agent. Four weeks after paclitaxel treatment, male mice were injected with a low dose of SBI-553. For over 24 hours, male mice showed a decrease in pain level by two metrics, an increase in the paw withdrawal threshold and increased time on the treadmill. Mechanical allodynia, or pain caused by slight stimuli such as a light touch, was reduced in mice injected with higher doses of SBI-553. SBI-553 also blocks the rewarding effects of psychostimulant drugs, including cocaine and methamphetamine, and opioids. At doses that reduce allodynia and blunt drug reward-related behaviors in mice, SBI-553 did not change body temperature or blood pressure.

Other Applications

This technology could also alleviate acute pain.

Advantages

• Non-opioid treatment for chronic pain via a long-investigated NTSR1 mechanism
• Reduces side effects associated with addictive drugs such as reward and motor enhancing effects
• Uses long sought-after neurotensin mechanism while bypassing the usual side effects associated with NTSR1 agonists, such as hypotension, hyperthermia, and motor impairment