Philippe Sitbon

A single dose of intrathecal morphine in rats induces long-lasting hyperalgesia: the protective effect of prior administration of ketamine.

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 &mgr;g and 10 &mgr;g) 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.

Gabapentin Prevents Delayed and Long-lasting Hyperalgesia Induced by Fentanyl in Rats

Background:Opioid-induced hyperalgesia can develop rapidly after opioid exposure. Neuropathic pain and opioid-induced hyperalgesia share common pathophysiologic mechanisms. Gabapentin is effective for the management of neuropathic pain and may therefore prevent opioid-induced hyperalgesia. This study tested the effectiveness of gabapentin for prevention of long-lasting hyperalgesia induced by acute systemic fentanyl in uninjured rats. Involvement of the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels in the prevention of opioid-induced hyperalgesia by gabapentin also was assessed. Methods:Hyperalgesia was induced in male Sprague-Dawley rats with subcutaneous fentanyl (four injections, 20, 60, or 100 &mgr;g/kg per injection at 15-min intervals). Intraperitoneal (30, 75, 150, or 300 mg/kg) or intrathecal (300 &mgr;g) gabapentin was administered 30 min before or 300 min after (intraperitoneal 150 mg/kg) the first fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed on the day of the experiment and for several days after injections. The effects combining gabapentin with intrathecal ruthenium red (20 ng) also were assessed. Results:Fentanyl administration was followed by an early increase (analgesia) and by a later and sustained decrease (hyperalgesia) in nociceptive thresholds. Gabapentin did not significantly modify the early analgesic component but dose-dependently prevented the delayed decrease in nociceptive threshold. Ruthenium red partially, but significantly, opposed the prevention of opioid-induced hyperalgesia by gabapentin. Conclusions:Intraperitoneal and intrathecal gabapentin prevents the development of hyperalgesia induced by acute systemic exposure to opioids. This prevention may result, at least in part, from binding of gabapentin to the &agr;2&dgr; auxiliary subunits of voltage-gated calcium channels.

Protective effect of prior administration of magnesium on delayed hyperalgesia induced by fentanyl in rats.

PurposeMagnesium exerts a physiological block of the ion channel on the N-methyl-D-aspartate receptor, and may therefore prevent the induction of central sensitization. The purpose of this study was to assess whether systemic magnesium can prevent long-lasting hyperalgesia induced by sc fentanyl administration in uninjured rats.MethodsLong-lasting hyperalgesia was induced in male Sprague Dawley rats with sc fentanyl (four injections, 60 μg·kg−1 per injection at 15-min intervals). Magnesium sulphate (100 mg·kg−1) was injectedip 30 min prior to the first sc fentanyl injection. Sensitivity to nociceptive stimuli (paw-pressure test) was assessed for several days after injections.ResultsSubcutaneous fentanyl led to delayed hyperalgesia associated with a decrease in the nociceptive threshold lasting two days (35% decrease for the maximum effect). Intraperitoneal magnesium sulphate partially but significantly (P < 0.05) prevented the delayed decrease in the nociceptive threshold following sc administration of fentanyl.ConclusionsThis study shows that magnesium may prevent the delayed and prolonged hyperalgesia following fentanyl administration in rats.RésuméObjectifLe magnésium exerce un blocage physiologique du récepteur N-méthyl-D-aspartate, et peut donc prévenir l’induction d’une sensibilisation centrale. Le but de cette étude était de déterminer si l’administration systémique de magnésium pouvait prévenir l’hyperalgésie prolongée induite par le fentanyl sc chez le rat naïf.MéthodeUne hyperalgésie prolongée était induite chez le rat mâle Sprague Dawley avec du fentanyl sc (quatre injections, 60 μg·kg−1 par injection à 15 min d’intervalle). Du sulfate de magnésium (100 mg·kg−1) était injecté par voie ip 30 min avant la première injection de fentanyl. La sensibilité aux stimuli nociceptifs (paw-pressure test) était évaluée durant plusieurs jours après les injections.RésultatsLe fentanyl a entraîné une hyperalgésie prolongée associée à une diminution du seuil nociceptif durant deux jours (diminution de 35 % de l’effet maximum). L’administration ip de sulfate de magnésium a prévenu partiellement mais significativement (P < 0,05) la diminution du seuil nociceptif secondaire à l’administration sc de fentanyl.ConclusionCette étude démontre que le magnésium peut prévenir l’hyperalgésie secondaire et prolongée après administration de fentanyl chez le rat.

The Median Effective Dose of Ketamine and Gabapentin in Opioid-Induced Hyperalgesia in Rats: An Isobolographic Analysis of Their Interaction

BACKGROUND: Ketamine and gabapentin have been shown to prevent the delayed hyperalgesia induced by short-term use of systemic opioids. The mechanism of this action is believed to be likely at the spinal level, through an antagonism of the N-methyl-d-aspartate receptors for ketamine, and through a specific binding site for gabapentin. In this study, we sought to determine the nature of the interaction of these 2 mechanistically distinct antihyperalgesic drugs in a model of opioid-induced hyperalgesia in rats. The median effective antihyperalgesic doses of each drug and of their combination were first defined, to assess the nature of the interaction using an isobolographic analysis. METHODS: Long-lasting hyperalgesia was induced in male Sprague Dawley rats with subcutaneous fentanyl (4 injections, 60 &mgr;g/kg per injection at 15-minute intervals) resulting in a total dose of 240 &mgr;g/kg. Subcutaneous ketamine, or intraperitoneal gabapentin, or their combination was administered 30 minutes before the first subcutaneous fentanyl injection. Sensitivity to nociceptive stimuli (von Frey filaments) was assessed on the day of the experiment and on the day after injections. The dose of ketamine and gabapentin received by a particular animal was determined by the response of the previous animal of the same group, using an up-and-down technique. Initial doses were 10 mg/kg and 300 mg/kg, with dose adjustment intervals of 1 mg/kg and 30 mg/kg, in the ketamine and gabapentin groups, respectively. The initial doses of ketamine and gabapentin were 5 mg/kg and 150 mg/kg, respectively, in the ketamine-gabapentin group, with the same dose adjustment intervals. Antihyperalgesic efficacy was defined as complete prevention of hyperalgesia on the day after drug injections. RESULTS: The median effective antihyperalgesic doses (median value and 95% confidence interval) of ketamine and gabapentin were 12.4 mg/kg (11.7–13.1 mg/kg) and 296.3 mg/kg (283.5–309.1 mg/kg), respectively. The median effective antihyperalgesic dose of the combination was 4.3 mg/kg (3.7–4.6 mg/kg) for ketamine and 123.9 mg/kg (111.1–136.7 mg/kg) for gabapentin. CONCLUSION: The isobolographic analysis demonstrated that the combination of the 2 drugs produces effective antihyperalgesia with a supraadditive (synergistic) action.

STR-324, a Stable Analog of Opiorphin, Causes Analgesia in Postoperative Pain by Activating Endogenous Opioid Receptor-dependent Pathways.

Background:Opiorphin is a naturally occurring potent analgesic human peptide. It protects enkephalins from degradation and inhibits pain perception in various acute pain models via activation of endogenous opioid pathways. However, the efficacy of opiorphin continuous infusion and its chemically stable form, STR-324, in postoperative pain is unknown. Methods:Using the Brennan model of plantar incision–induced hypersensitivity, the authors examined the postsurgical analgesic response to mechanical and thermal stimuli of 7-day continuously intravenously infused drugs (8 to 10 rats per group). Antinociception from opiorphin with reference to morphine and STR-324 was assessed. Spinal c-Fos expression and the involvement of opioid receptor–dependent pathways were investigated. The occurrence of respiratory and hemodynamic adverse effects of opiorphin was also tested. Results:Intravenous infusion of opiorphin significantly reduced responses to mechanical stimuli from days 1 to 4 post surgical period at 143 to 175-kPa mean ranges compared with 23 to 30-kPa mean ranges for vehicle (P < 0.05). During the 3-day postoperative period, no respiratory rate, oxygen saturation, arterial pressure, or heart rate adverse effects were induced by opiorphin. STR-324 consistently inhibited mechanical and thermal hyperalgesia with similar potency as that of opiorphin. Mechanistic analyses demonstrated that the STR-324 antinociceptive effect was reversed by the opioid antagonist, naloxone. Also, STR-324 significantly reduced the number of pain-evoked spinal cFos-immunoreactive nuclei. Conclusion:Intravenous infusion of opiorphin and STR-324 produced significant antinociceptive effect in a postoperative pain model. This study demonstrates that STR-324 is effective in postoperative pain management due to its strong antihyperalgesic effects mediated via opioid-dependent antinociceptive pathways. Opiorphin analog should represent a new class of potent and safe analgesics.