Antinociceptive effects and toxicity of morphine-6-O-sulfate sodium salt in rat models of pain

Mu-opioids (i.e. morphine, oxycodone, hydrocodone) are considered to be the primary drugs for treatment of moderate to severe acute, chronic and cancer pain. Despite their analgesic effectiveness they have several clinically significant side-effects (cognitive, motor, respiratory, cardiovascular, gastrointestinal). They also have a limited spectrum of action, being more effective for nociceptive than neuropathic pain. In an effort to identify other opioid analgesics with greater effectiveness in mixed pain states and with a better side-effect profile compared to the classical mu-opioid agonist, morphine, a relatively little-known morphine derivative, morphine-6-O-sulfate, was characterized using a range of well-established rodent pain models. The present data demonstrated that morphine-6-O-sulfate was efficacious after several routes of administration, including neuroaxial (intrathecal), parenteral (intraperitoneal) and oral in the rat. It showed potent, dose-related, analgesic activities against acute nociceptive pain (the tail flick test), neuropathic pain (chronic constriction nerve injury hyperalgesia and allodynia) and inflammatory pain (formalin test). It had a good separation based on dose (at least 10-fold) between side-effects (incoordination, hypolocomotion, inhibition of gastrointestinal motility) and analgesia in all models of pain tested. In addition, morphine-6-O-sulfate had a more favorable potency ratio for delay of gastrointestinal transit and analgesia when compared to morphine. These preclinical findings suggest that morphine-6-O-sulfate is a potential candidate for development as a novel opioid for management of nociceptive, neuropathic and mixed pain states.