Abstract
Oxycodone is a μ-opioid receptor agonist, used for the treatment of a large variety of painful disorders. Several studies have reported that oxycodone is a more potent pain reliever than morphine, and that it improves the quality of life of patients. However, the neurobiological mechanisms underlying the therapeutic action of these two opioids are only partially understood. The aim of this study was to define the molecular changes underlying the long-lasting analgesic effects of oxycodone and morphine in an animal model of peripheral neuropathy induced by a chemotherapic agent, vincristine. Using a behavioural approach, we show that oxycodone maintains an optimal analgesic effect after chronic treatment, whereas the effect of morphine dies down. In addition, using DNA microarray technology on dorsal root ganglia, we provide evidence that the long-term analgesic effect of oxycodone is due to an up-regulation in GABAB receptor expression in sensory neurons. These receptors are transported to their central terminals within the dorsal horn, and subsequently reinforce a presynaptic inhibition, since only the long-lasting (and not acute) anti-hyperalgesic effect of oxycodone was abolished by intrathecal administration of a GABAB receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABAB receptor is functionally required for the alleviating effect of oxycodone in neuropathic pain condition, thus providing new insight into the molecular mechanisms underlying the sustained analgesic action of oxycodone.
Highlights
7–8% of the European population suffers from neuropathic pain, and 5% of these cases may be severe [1]
The aim of this study was two-fold: to better understand the mechanisms underlying the analgesic effect of both oxycodone and morphine; and to compare these mechanisms of action in a model of neuropathic pain induced by vincristine
Our results demonstrate that a large number of genes are dysregulated after opioid analgesic treatment in vincristine-treated animals
Summary
7–8% of the European population suffers from neuropathic pain, and 5% of these cases may be severe [1]. The pharmacotherapy of neuropathic pain is frequently unsatisfactory for patients. One reason for their poor efficacy is the lack of a clear understanding of the neurobiological mechanisms that underlie neuropathic pain. Oxycodone shows excellent anti-hyperalgesic and antiallodynic effects against neuropathic pain [2,3]. Like other opioids, including morphine, the analgesic effect of oxycodone is mainly mediated through the activation of the m-opioid receptor. In patients with neuropathic pain, oxycodone treatment (mostly in combination with anticonvulsants) improves health-related quality of life and diminishes the impact of pain on physical activity and sleep [11]. The aim of this study was to identify the molecular changes that produce the different analgesic effects of morphine and oxycodone
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