Proof-of-concept opioid/dopamine combination therapy for SCI-related pain Grant uri icon

abstract

  • We have previously shown that experimental excitotoxic spinal cord injury (SCI) induces thermal hyperalgesia and reduces subsequent analgesic actions of morphine in morphine-na?ve rodents, and we have recently demonstrated this same phenomenon after traumatic (contusion) SCI. As spinal dopamine (DA) function is compromised after SCI, we assessed the roles of DA D3 (D3R) and DA D1 (D1R) receptors on opioid responsiveness. We found that a dysfunction of the spinal D3R system led to opioid ineffectiveness providing analgesia similar to that seen after SCI. Importantly, adjuvant treatment of morphine with a D3R agonist or a D1R antagonist augmented opioid effectiveness. We are able to reduce opioid-effectiveness in the isolated spinal cord by acutely blocking the D3 receptor, and have shown that mice lacking the functional D3 receptor (D3KO) have higher ratio of phosphorylated mu-opioid receptors (MORs)/total MOR compared to wild-type (WT) controls, suggesting that intracellular signaling through the MOR receptor may be altered in the face of DA receptor dysfunction. Based on these and other data we hypothesize that through manipulation of the DA receptor system, we can acutely restore morphine effectiveness and prevent the development of opioid resistance in the long-term treatment of chronic neuropathic pain associated SCI with adjuvant therapy of clinically-available D3R agonists or D1R antagonists, reducing the risk of tolerance and potential addiction to opioid analgesics. The purpose of this proposal is to provide proof-of-concept that adjuvant therapy with clinicallyavailable dopamine receptor modulators can enhance the analgesic effects of morphine in the treatment of chronic neuropathic pain associated with SCI while minimizing the risk of addiction. We will do this through the following Specific Aims: 1) Demonstrate in vivo that a combination of opioids and D3R agonists or D1R antagonists provides superior analgesia for neuropathic pain associated with SCI, but does not induce the motivation effects seen with morphine alone. 2) Demonstrate in vivo that adjuvant treatment with D3 agonists or D1 antagonists will allow morphine to maintain its effects over time and prevent the need for escalating doses of morphine to achieve analgesia with chronic exposure (i.e. prevent morphine tolerance) and 3) Confirm in vivo and in the isolated spinal cord that altering D3R or D1R activity in the spinal cord creates an altered functional state of the MOR as well as the function of the other DA receptor and controls activity changes of the cAMP/PKA-mediated second messenger pathways.

date/time interval

  • October 2016 - January 2020