Peroxynitrite Decomposition Catalysts as Adjuncts to Morphine for the Management of Chronic Pain States

Abstract

Severe pain reduces life quality in patients with inflammatory and neoplastic diseases (i.e lung cancer), partly because reduced analgesic effectiveness of chronic opiate therapy leads to escalating doses and distressing side effects. The mechanisms involved are poorly understood. Peroxynitrite (ONOO−), a potent pro‐inflammatory and pro‐apoptotic reactive species, is now implicated in hyperalgesia of several etiologies. In mice we showed that repeated morphine administration leads to nitrotyrosine (NT) formation in the dorsal horn of the spinal cord, with NT as a reliable marker for ONOO−. The role of ONOO− was proven by showing that co‐administering morphine with novel and potent ONOO− decomposition catalysts such as Mn(III) ortho alkylpyridylporphyrins, attenuated NT formation and prevented antinociceptive tolerance at doses devoid of behavioural side effects and up to 300 fold‐lower than previously used Fe or Mn porphyrins. These effects coincided with: 1) nitration of MnSOD, a glutamate transporter, and glutamine synthase; 2) increased formation of pro‐inflammatory cytokines; and 3) oxidative DNA damage and activation of the nuclear factor poly(ADP‐ribose) polymerase. These findings support our central hypothesis that ONOO− is critical to the development of morphine‐induced antinociceptive tolerance providing the rationale towards the development of ONOO− decomposition catalysts as adjuncts to opiates for the management of chronic pain.