(283) Adjuvant Treatment with Dopamine Receptor Modulators Prevents the Development of Morphine Tolerance in a Rodent Model

Abstract

Opioids have a prominent role in managing acute pain. However, long-term management of pain with opioids is complicated, as tolerance for the drug develops, increasing the risk for misuse and abuse. The need exists for chronically effective treatments that minimize the rewarding component. Our data shows that, in animal models, combining low-dose morphine with a dopamine 3 receptor (DR3) agonist or dopamine 1 receptor (D1R) antagonist provides superior analgesia against acute painful stimuli compared to morphine alone. The current study examined if adjuvant treatment with D3R agonists or D1R antagonists can also prevent the development of tolerance to and reduce the addictive potential of morphine. Thermal and mechanical thresholds were tested in 16, female Long-Evans rats before and after a single subcutaneous dose of morphine (2mg/kg). Rats were then randomized to 1 of 4 chronic drug conditions: saline; morphine (5mg/kg/day); morphine + pramipexole (D3R agonist, 0.1mg/kg/day); morphine + SCH39166 (D1R antagonist, 0.1mg/kg/day). Drugs were delivered for 14 days via subcutaneous osmotic pump. Analgesia provided by an acute dose of morphine was re-assessed at 7 and 14 days after initiation of drug delivery. Addictive potential of each drug combination was determined using conditioned place preference (CPP). Prior to drug delivery, acute morphine injection increased thermal and mechanical thresholds in all animals. Fourteen days after chronic administration of morphine, sensory thresholds did not change in response to acute morphine (i.e. animals were tolerant). In contrast, sensory thresholds were increased in animals that had received morphine in combination with either dopamine receptor modulator. The addition of either dopamine receptor modulator to morphine also reduced the preference for the drug compared to morphine alone. Adjuvant therapy with clinically-available dopamine receptor agonists or antagonists can prevent the development of morphine tolerance and reduce the rewarding effect of morphine alone.