Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

TY - JOUR

T1 - Molecular Mechanisms Underlying the Enhanced Analgesic Effect of Oxycodone Compared to Morphine in Chemotherapy-Induced Neuropathic Pain

AU - Thibault, Karine

AU - Calvino, Bernard

AU - Rivals, Isabelle

AU - Marchand, Fabien

AU - Dubacq, Sophie

AU - McMahon, Stephen B.

AU - Pezet, Sophie

PY - 2014/3/11

Y1 - 2014/3/11

N2 - Oxycodone is a m-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 GABA(B) 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 GABA(B) receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABA(B) 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.

AB - Oxycodone is a m-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 GABA(B) 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 GABA(B) receptor antagonist; in contrast, the morphine effect was unaffected. Our study demonstrates that the GABA(B) 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.

KW - VINCRISTINE-INDUCED NEUROPATHY

KW - CONTROLLED-RELEASE OXYCODONE

KW - GENE-EXPRESSION

KW - CANCER PAIN

KW - SPINAL-CORD

KW - RECEPTOR SUBUNITS

KW - BRAIN-REGIONS

KW - RAT MODEL

KW - HYPERALGESIA

KW - INHIBITION

U2 - 10.1371/journal.pone.0091297

DO - 10.1371/journal.pone.0091297

M3 - Article

SN - 1932-6203

VL - 9

JO - PL o S One

JF - PL o S One

IS - 3

M1 - e91297

ER -