Highly Potent Mu Opioid Receptor Ligands Derived from Salvinorin A
Novel ligands designed to activate mu opioid receptors and provide analgesic effects without opioid-related side effects, providing specific insight into the cellular impact of opioid receptor-based activation as related to pain medications. These ligands could be used as a tool to negate drug tolerance and dependence as well as other adverse side effects.
Opioid drugs are widely used for the management of severe or chronic pain. Although highly effective, opioid-based analgesics are associated with a plethora of side effects including sedation, constipation, respiratory depression as well as tolerance and dependence. Drug overdose is now the leading cause of accidental death in the U.S. and opioid painkillers are driving this epidemic.
Morphine and its compound derivatives including codeine, oxycodone, meperidine, methadone, and fentanyl are mu-opioid receptor (MOR) agonists with powerful analgesic effects. These drugs interact with opioid receptors on nerve cells in the brain and nervous system to block the transmission of pain signals. In doing so, these drugs alleviate pain and produce pleasurable effects. Activation of these opioid receptors triggers numerous downstream events. Although the mechanism for opioid-based analgesia has been defined, the pathways involved in the aforementioned side effects are not well understood.
Develop new drugs for the management of severe or chronic pain, elucidate the role of mu opioid receptors with regard to specific analgesic effects (blocking of neurotransmitters) versus downstream cellular events that contribute to drug tolerance and dependence, as well as other side effects including respiratory depression and constipation.
How it works:
These ligands were designed to bind to opioid receptors on the surface of nerve cells and block the transmission of pain signals as in the case of opioid-based drug compounds. Furthermore, these ligands activate opioid receptors without recruiting β-arrestin-2, which is thought to be involved in tolerance, constipation, and respiratory suppression associated with opioid pain medications. Interestingly, these ligands showed comparable potency to morphine with reduced tolerance, motor impairment, and propensity for dependence in preliminary animal studies.
- Specificity and selectivity for mu opioid receptors in vitro and in vivo.
- Potent analgesic effect when administered in vivo in an animal model.
- Reduced side effects in comparison to morphine: no tolerance or dependence and reduced motor impairment.
- Could ultimately allow for the development of new medications for the treatment of severe or chronic pain without the propensity for developing tolerance or dependence.
Why it is better:
Currently, relatively few treatment options exist for pain management. Opioids comprise the most powerful class of analgesics with indications for chronic or severe pain. The widespread use of opioid medications is largely attributed to the comorbidity of chronic pain with several major conditions including cancer, arthritis, and diabetes. However, in addition to several adverse side effects, the widespread use of prescription opioids has correlated with significant tolerance and dependence. This, in turn, has driven opioid drug use and addiction to epidemic proportions. The technology described herein could serve as a tool for distinguishing between the analgesic effects of opioid-receptor stimulation versus downstream events that are responsible for the adverse and unwanted effects of opioid medications.