Peroxynitrite: a strategic linchpin of opioid analgesic tolerance

Severe pain syndromes reduce quality of life in patients with inflammatory and neoplastic diseases, partly because the reduced analgesic effectiveness accompanying chronic opiate therapy (i.e. tolerance) leads to escalating doses and distressing side effects. Accordingly, there is major interest in new approaches to maintain opiate efficacy during repetitive dosing without engendering tolerance or causing unacceptable side effects. Recent mounting evidence implicates nitroxidative stress caused by the presence of superoxide (O2−), nitric oxide (NO) and subsequently peroxynitrite (ONOO−) in opiate analgesic tolerance. Here, we provide a pharmacological basis for developing inhibitors of ONOO− biosynthesis and/or ONOO− scavengers as potent adjuncts to opiates in the management of chronic pain, addressing an issue of major clinical and socio-economic importance while laying the basis for interventions with strong therapeutic potential.