Preclinical assessment of acute and chronic treatment with novel endomorphin analogs for pain
Description
Opioids are the gold standard for treatment of severe pain, but long-term use of opioids has led to a crisis of addiction and overdose deaths in the US and abroad. Additionally, long-term use of opioids can lead to worse pain, dependence, and a host of other unfavorable side effects. ZH853 is a novel endomorphin analog that has reduced side effects, including abuse liability, and superior analgesia compared to morphine. The studies contained in this work examine the acute effectiveness of ZH853 in several pain states and whether chronic use prolongs and intensifies pain as morphine does. Two treatment paradigms were investigated. Either 1) chronic pain was induced followed by chronic treatment with morphine, ZH853 or vehicle, or 2) chronic drug was administered prior to pain induction. Neuropathic, inflammatory, and postoperative pain were induced using well-characterized methods. Drugs were administered by minipumps for 3-5 days at appropriate doses based on prior experiments. Animals were tested for mechanical allodynia and thermal hyperalgesia using von Frey filaments and the Hargreaves apparatus, respectively. Additionally, several gait parameters were measured using the CatWalk XT. At the end of experiments when animals had recovered to baseline, a naltrexone injection was administered to unmask latent sensitization (LS). Additional animals were used for immunohistochemistry (IHC) to assess several markers involving pain and inflammation. Morphine increased and prolonged inflammatory and postoperative pain while ZH853 reduced the overall time spent in pain and the severity of pain scores. Markers of inflammation were increased in morphine-treated animals but ZH853-treated animals consistently showed minimal inflammation. Finally, ZH853 protected against LS in all experiments, while vehicle- and morphine-treated animals showed hyperalgesia following naltrexone administration. ZH853 has a favorable side effect profile versus morphine, including greatly reduced abuse liability and a lack of respiratory depression, and it provides superior analgesia in a number of pain states. We now know that chronic use of this compound reduces time spent in a chronic pain state, the opposite of common opioids like morphine, making ZH853 an excellent candidate for clinical development in humans for chronic pain.