M.-A. Docquier

Can determining the minimum alveolar anesthetic concentration of volatile anesthetic be used as an objective tool to assess antinociception in animals

We intended to evaluate the reliability of the minimum anesthetic alveolar concentration (MAC)-sparing effect as an objective measure of the antinociceptive properties of a drug. For this purpose, we tested different variables and analyzed the significance of the results obtained. In a first set of experiments, we studied rats under mechanical ventilation and sevoflurane anesthesia. Outcome variables such as gross purposeful movements consecutive to tail clamping, paw withdrawal consecutive to increasing pressure, and cardio-circulatory reactivity (MACBAR) after these stimuli were recorded. In a second set of experiment, sevoflurane-anesthetized rats under spontaneous breathing conditions were used. Thermal stimuli were compared with pressure. The MAC-sparing effect of several doses of sufentanil and clonidine was evaluated in both anesthetized and awake rodents. When considering the stimulus applied, larger concentrations of sevoflurane were required to suppress reactivity after tail clamp than after paw pressure or radiant heat (1.81 ± 0.28 versus 1.45 ± 0.22 and 1.53 ± 0.26; P < 0.05). For the two first stimuli, no significant differences were noted between the concentrations that suppress motor or cardio-circulatory reactions. All doses of sufentanil tested significantly reduced (P < 0.05) the different MAC values except the smallest one (0.005 &mgr;g · kg−1 · min−1) that significantly increased MACBAR in ventilated animals and both MAC and MACBAR in spontaneously breathing rodents (P < 0.05). Clonidine, at its optimal dose (10 &mgr;g/kg), significantly reduced both MAC and MACBAR to the same degree. In awake animals submitted to radiant heat or pressure challenge, none of the clonidine doses nor sufentanil doses (0.005 and 0.07) were active. In conclusion, the MAC-sparing effect provides several reliable and quantifiable variables that allow comparison between different analgesic substances. However, the observations made are not simply the result of antinociceptive effects of the tested drugs but rather that of complex interactions between these drugs and a halogenated vapor.

Spinal alpha(2)-adrenoceptors are involved in the MACbar-sparing effect of systemic clonidine in rats.

UNLABELLED We evaluated the central or spinal mechanism involved in the MACbar-sparing effect of systemic clonidine by using intrathecal alpha-adrenergic antagonist administration. The minimum alveolar concentration of sevoflurane that blocks cardiovascular response to a noxious stimulus (MACbar(sevo)) was determined in rats after treatment with IV saline, IV clonidine 10 micro g/kg, intrathecal (IT) or IV phentolamine 50 micro g, IT or IV yohimbine 200 micro g, IT or IV prazosin 30 micro g, or the combination of IV clonidine and the different IT or IV alpha-adrenergic antagonists. In the studied model, the MACbar(sevo) of saline-treated controls was 2.10 +/- 0.8. After clonidine administration, it decreased to 1.07 +/- 0.4. The IT administration of phentolamine and yohimbine did not modify the MACbar(sevo) of naïve rats, whereas in IV clonidine-treated animals, it totally suppressed the MAC-sparing effect of this drug (phentolamine) or even significantly increased (yohimbine) the MACbar(sevo) (2.78 +/- 1) when compared with controls (P < 0.05). IT prazosin alone significantly reduced the MACbar(sevo) (0.35 +/- 0.3; P< 0.05) and suppressed any hemodynamic reaction when combined with IV clonidine. The IV administration of the different alpha-adrenergic antagonists had no significant effect on the MACbar(sevo) of controls or IV clonidine-treated animals. These results argue for a spinal mechanism of action involved in the MACbar-sparing effect of systemic clonidine. Moreover, the spinally administered alpha-antagonists displayed different effects in rats under sevoflurane anesthesia than those reported in awake animals. IMPLICATIONS Using intrathecal alpha-adrenergic antagonist administration, we demonstrated that a spinal mechanism is involved in the MACbar-sparing effect of systemic clonidine in rats.

Longlasting hyperalgesic effects of intraoperative high dose of fentanyl in a new animal model of persistent postoperative pain: 14AP1-8

(Met-ENK), Leu-ENK or dynorphin A (DYN); b) selective antagonists of mu(CTOP), delta(ICI 174.864) and kappa(nor-binaltorphimine; norBNI) opioid receptors; c) peripherally restricted opioid receptor antagonist (naloxone methiodide; NLXM). The antinociceptive effects of RB 3008 were also assessed after pretreatment with Cyclosporin A (CSA) intraperitoneally. Results and Discussion: NEP, APN and the opioid peptides beta-endorphin, Metand Leu-enkephalin were expressed in leukocytes in inflamed paws. Coinjection of thiorphan and bestatin or application of RB3008 into inflamed paws inhibited mechanical hyperalgesia. These antinociceptive effects were reversed by local pre-treatment with antibodies against beta-endorphin, Metand Leu-enkephalin and dynorphin A, with selective mu-, deltaand kappareceptor antagonists and with the peripherally restricted opioid receptor antagonist naloxone-methiodide. Also, RB3008-induced antinociception was blocked by immunosuppression with cyclosporin A, suggesting that NEP/APN blockade promotes analgesia by immune cell-derived opioids. Conclusion(s): 1. NEP, APN and opiod peptides are present in immune cells accumulating in inflamed tissue. 2. Single (bestatin and thiorphan) and a novel dual (RB 3008) enkephalinase inhibtiors produce analgesia via opioid peptides acting at peripheral opioid receptors directly in inflamed tissue. 3. NEP/APN blockade promotes analgesia by leukocyte-derived opioids. 4. Preventing the degradation of endogenous opioids in injured tissues offers an interesting strategy for control of inflammatory pain.

Analgesic and hyperalgesic effect of single intrathecal dose of morphine under normal and neuropathic conditions: 14AP2-10

plasma O2 . production was the highest at the just reperfusion and lasted at least 1 week. Mechanical and cold allodynia were present in both hindpaws as early as 4 hr after reperfusion, and lasted at least 4 weeks. Pain behavior was significantly attenuated in G1, G2 and G3 compared with control. In G3, pain behavior was less attenuated than G1 and G2. Microscopic findings showed less inflammatory reaction in the G1 and G2. Conclusion(s): This study suggests that the O2 . is partly responsible for development of the CRPS-I. Even though O2 . inhibition is less effective after CRPS-I has been already developed, O2 . inhibition is still effective for reduce CRPS-I pain. References: 1 White FA, Bhangoo SK, Miller RJ. Nat Rev Drug Discov 2005; 4: 834–44. 2 Kim HK, Park SK, Zhou JL, et al. Pain 2004; 111: 116–24. 3 Coderre TJ, Xanthos DN, Francis L, et al. Pain 2004; 112: 94–105.