Neurobiology of the Opioid Epidemic: Basic and Translational Perspectives

Repeated morphine exposure activates synaptogenesis and other neuroplasticity-related gene networks in the dorsomedial prefrontal cortex of male and female rats

“…Investigations into the cellular, molecular, and genetic effects of opioid administration have undergone rapid progress (Imperio et al, 2016;Valentino et al, 2020). Nevertheless, while a number of molecular targets that play key roles in opioid addiction have been identified (Browne et al, 2020;Hurd and O'Brien, 2018), the ways in which a broader range of functional pathways and networks interact to produce and/or maintain addictive behavior remain to be determined.…”

Overdose mortality rates for opioids or stimulants are higher in males than females, controlling for rates of drug misuse: State-level data

“…Furthermore, even within these major categories, the pharmacodynamics and pathophysioIogical effects of fentanyl vs heroin and other -agonists [29,30,87], or methamphetamine vs cocaine [36,39,88], are not necessarily identical. Instead, multiple sex-or gender-related mechanisms, potentially with different expressions/contributions, could underlie the risk of overdose mortality, at different stages in the life-long trajectories of these substance use disorders [24,35,[89][90][91][92][93]. At a behavioral level, men could more frequently reach patterns of drug exposure associated with greater overdose risk (e.g., due to high doses, or frequency of use) despite negative consequences such as withdrawal (e.g., sex differences in positive or negative reinforcement) [94,95].…”

Analgesic Opioid Ligand Discovery Based on Nonmorphinan Scaffolds Derived from Natural Sources

“…In the clinical setting, strong opioid analgesics such as morphine ( 1 ) (Figure ) are the drugs of choice for alleviating moderate to severe acute pain and chronic cancer pain . Their use for the treatment of chronic noncancer pain is controversial because of the “opioid crisis” characterized by opioid misuse or abuse and escalating unintentional death rates due to overdose-related respiratory depression. , However, there are differences in the spectrum of opioid-related adverse effects mediated by MOP, DOP, and KOP receptors . Typically, MOP receptor agonists evoke nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability. ,, DOP receptor agonists may evoke physical dependence and convulsions, , whereas KOP receptor agonists are associated with dysphoria, sedation, diuresis, and hallucinations …”

“…9 Their use for the treatment of chronic noncancer pain is controversial because of the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to overdose-related respiratory depression. 10,11 However, there are differences in the spectrum of opioid-related adverse effects mediated by MOP, DOP, and KOP receptors. 6 Typically, MOP receptor agonists evoke nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability.…”

“…6,9,12 DOP receptor agonists may evoke physical dependence and convulsions, 6,13 whereas KOP receptor agonists are associated with dysphoria, sedation, diuresis, and hallucinations. 6 Based on their chemical structure, clinically used opioid analgesics belong to one of six main chemotypes, namely the morphinans (e.g., morphine (1), hydromorphone (3), hydrocodone (4), oxycodone (5), oxymorphone (6), codeine (7), nalbuphine (8), and butorphanol ( 9)), the orvinols (e.g., buprenorphine (10a), etorphine (10b), and diprenorphine (10c)) (Figure 3), the piperidines and anilinopiperidines (e.g., pethidine (11), loperamide (12), fentanyl (13), alfentanil (14), sufentanil (15), and remifentanil ( 16)) (Figure 4), the open-chains (e.g., methadone (17)), the benzenoids (tramadol (18) and tapentadol (19)), and oliceridine (20) (Figure 5). 7 Although opioid antagonists are also used clinically and in research studies, they are outside the scope of this Perspective.…”