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PAIN MEDICINE

A Single Dose of Intrathecal Morphine in Rats Induces Long-Lasting Hyperalgesia: The Protective Effect of Prior Administration of Ketamine

Department of Anesthesiology, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris and the Anesthesia Laboratory UPRES-EA 3540, Faculté de Médecine du Kremlin-Bicêtre Université Paris-Sud, Le Kremlin-Bicêtre, France

Address correspondence to Philippe Sitbon, MD, Service d’Anesthésie-Réanimation, Hôpital de Bicêtre, 94275 Le Kremlin-Bicêtre, France. Address e-mail to philippe.sitbon{at}bct.ap-hop-paris.fr.

An active pronociceptive process involving N-methyl-d-aspartate (NMDA) receptor activation is initiated by opioid administration, leading to opioid-induced pain sensitivity. Experimental observations in rats have reported reduction of baseline nociceptive threshold after prolonged spinal opioid administration. In this study we sought to determine whether a single dose of intrathecal morphine can induce hyperalgesia in uninjured rats and to assess the effects of pretreatment with the NMDA-antagonist ketamine on nociceptive thresholds. Sensitivity to nociceptive stimuli (paw pressure test) was assessed for several days after an acute intrathecal injection of morphine (5 µg and 10 µg) in male Sprague-Dawley rats. The effects of subcutaneously administered NMDA-receptor antagonist ketamine (10 mg/kg) before intrathecally administered morphine were also evaluated. A single intrathecal injection of morphine led to a biphasic effect on nociception; early analgesia associated with an increase in the nociceptive threshold lasting 3-5 h was followed by delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting 1-2 days. Subcutaneous ketamine did not significantly modify the early analgesic component but almost completely prevented the delayed decrease in nociceptive threshold after intrathecal administration of morphine. A single intrathecal injection of morphine in rats produces a delayed and sustained hyperalgesia linked to the development of opioid-induced pain sensitivity.

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