Medical use of opioids is essential to treat acute postoperative pain and for different types of chronic pain conditions. However, opioid therapies are associated with complex side effects that are challenging to manage. Long-term use often leads to tolerance, resulting in undertreatment of pain, difficulties estimating a safe dose escalation, and increased risk for overdose. Opioid therapy can also cause opioid-induced hyperalgesia (OIH), a paradoxical painful condition state where patients experience diffused increased sensitivity to pain, often unrelated to the original pain (Lee, Silverman, Hansen, Patel, & Manchikanti, 2011). The opioid epidemic, caused by over-prescription, continues to increase numbers of patients addicted to opioids, as well as users transitioning to heroin and other drugs (Blanco & Volkow, 2019). It is estimated that more than hundred deaths every day in the United States are caused by misuse or opioid overdose (Hser et al., 2019). Although it is generally assumed that physiological homeostatic adaptations cause these side effects, little is known about their underlying molecular and cellular mechanisms.Inside the body, morphine is metabolized into the two main active metabolites morphine-3-glucuronide (M3G) and morphine-6glucuronide (M6G). M6G is found at lower plasma concentration than M3G, but has much higher analgesic potency than M3G ( 200