SCI-INDUCED MORPHINE TOLERANCE IS ASSOCIATED WITH DOPAMINE PATHWAY EXPRESSION

Abstract

Opioids are commonly prescribed to relieve neuropathic pain after a spinal cord injury (SCI),4 but often fail to be effective due to an injury-induced state that mimics opioid tolerance.22 Previous studies have shown that the analgesic effects of morphine can be restored if morphine is administered in combination with a dopamine D3 receptor agonist or a dopamine D1 receptor antagonist, demonstrating that dopamine receptor activity modulates the response to opioids after SCI.5 Therefore, it was hypothesized that SCI alters levels of dopamine and expression of its receptors in the brain and spinal cord and that these changes are associated with injury-induced morphine tolerance. Baseline nociceptive (pain) thresholds were measured in 8 uninjured and 16 spinal cord injured rats before and after injection of morphine (2mg/kg) or saline (control). Rats were then randomized to have thresholds re-assessed after injection of morphine + pramipexole (PPX, D3 agonist), morphine + SCH 39166 (SCH, D1 antagonist), pramipexole, or SCH. Lumbar spinal cord and striatal brain tissue were collected from each animal and processed for metabolomics, targeted mass spectrometry (MS) and Western blot to identify, quantify and compare levels of dopamine and its metabolites and receptors across groups. Morphine alone increased sensory thresholds in all uninjured but only 33% of injured rats. Based on this data, animals were categorized as morphine responders (n=5) or nonresponders (n=10). Morphine + PPX and morphine + SCH increased sensory thresholds in all injured animals, while PPX and SCH alone had no effect. Striatal dopamine levels in injured morphine nonresponders were significantly decreased compared to uninjured animals. Dopamine levels in injured morphine responders compared to injured morphine nonresponders are currently being analyzed further. Metabolomics principal component analysis (PCA) of lumbar cord identified three clusters that corresponded to injured morphine responders, injured morphine nonresponders, and uninjured animals. Preliminary pathway analysis points to differences in phenylalanine, tyrosine, and tryptophan biosynthesis between these groups. Full pathway analysis is ongoing, but data suggests that differential dopaminergic pathway expression in the CNS following SCI is associated with morphine responsiveness. This provides early evidence that the dopamine system may provide a target for intervention in opioid resistant pain states.