Peptide-derived ligands for the discovery of safer opioid analgesics.

Drugs targeting the μ-opioid receptor (MOR) remain the most efficacious analgesics for the treatment of pain, but activation of MOR with current opioid analgesics also produces harmful side effects, notably physical dependence, addiction, and respiratory depression. Opioid peptides have been accepted as promising candidates for the development of safer and more efficacious analgesics. To develop peptide-based opioid analgesics, strategies such as modification of endogenous opioid peptides, development of multifunctional opioid peptides, G protein-biased opioid peptides, and peripherally restricted opioid peptides have been reported.

NCP, a Dual Kappa and Mu Opioid Receptor Agonist, Is a Potent Analgesic Against Inflammatory Pain without Reinforcing or Aversive Properties.

While agonists of (MOR) and (KOR) opioid receptors have analgesic effects, they produce euphoria and dysphoria, respectively. Other side effects include respiratory depression and addiction for MOR agonists and sedation for KOR agonists. We reported that 17-cyclopropylmethyl-3,14-dihydroxy-4,5-epoxy-6-{[4'-(2'-cyanopyridyl)]carboxamido}morphinan (NCP) displayed potent KOR full agonist and MOR partial agonist activities (58%) with 6.

Paternal morphine exposure enhances morphine self-administration and induces region-specific neural adaptations in reward-related brain regions of male offspring.

Background: A growing body of preclinical studies report that preconceptional experiences can have a profound and long-lasting impact on adult offspring behavior and physiology. However, less is known about paternal drug exposure and its effects on reward sensitivity in the next generation.

Methods: Adult male rats self-administered morphine for 65 days; controls received saline.

A novel Oprm1-Cre mouse maintains endogenous expression, function and enables detailed molecular characterization of μ-opioid receptor cells.

Key targets of both the therapeutic and abused properties of opioids are μ-opioid receptors (MORs). Despite years of research investigating the biochemistry and signal transduction pathways associated with MOR activation, we do not fully understand the cellular mechanisms underlying opioid addiction. Given that addictive opioids such as morphine, oxycodone, heroin, and fentanyl all activate MORs, and current therapies such as naloxone and buprenorphine block this activation, the availability of tools to mechanistically investigate opioid-mediated cellular and behavioral phenotypes are necessary.