Nitrous oxide revisited - Evidence for potent antihyperalgesic properties
ABSTRACT Although opioids are unsurpassed analgesics for surgery, they also induce an N-methyl-D-aspartate-dependent enhancement of postoperative hyperalgesia. Because nitrous oxide (N2O) has anti-N-methyl-D-aspartate properties, the purpose of this study was to evaluate nitrous oxide ability to prevent such an opioid-induced hyperalgesia in rats.
First, preventive effects of 50/50% N2O-O2 on the development of delayed hyperalgesia observed after inflammatory pain (hind paw carrageenan injection on D0) were examined for several days. Second, the ability of nitrous oxide (10-40%) to limit opioid-induced hyperalgesia induced by fentanyl was evaluated in nonsuffering rats. Third, antihyperalgesic effects of various nitrous oxide concentrations (20-50%) were assessed in both inflammatory and incisional pain models in fentanyl-treated rats (4 x 100 microg/kg subcutaneously). Finally, the analgesic effect of a single dose of morphine was evaluated 24 h after fentanyl administration and nitrous oxide (D0) to assess its preventive effect on acute morphine tolerance in both nonsuffering and hind paw-incised rats.
When applied on D0, nitrous oxide reduced delayed hyperalgesia induced by inflammation. Exposure to nitrous oxide on D0 also reduced opioid-induced hyperalgesia in nonsuffering rats in a dose-dependent manner. In fentanyl-treated rats with inflammatory or incisional pain, nitrous oxide strongly limited both magnitude and duration of hyperalgesia. Moreover, nitrous oxide exposure on D0 opposed development of acute tolerance to analgesic effects of morphine administered on D1 in both nonsuffering and incised fentanyl-treated rats.
Nitrous oxide, an N-methyl-D-aspartate receptor antagonist, prevented the enhancement of pain sensitivity induced by both nociceptive inputs and fentanyl and opposed acute morphine tolerance. Results suggest that perioperative nitrous oxide use reduces exaggerated postoperative pain and morphine consumption.
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- "Alternatively, N 2 O inhalation may oppose the learned acquisition of CCRs because this drug antagonizes neuronal signaling mediated via the NMDA receptor (Jevtovic-Todorovic et al., 1998)), a phenomenon of vital importance to learning and memory (Li and Tsien, 2009). Consistent with this possibility, N 2 O exposure was reported to counter drug adaptations with a demonstrated dependence on intact NMDA signaling, specifically the development of acute tolerance to morphine analgesia and the development of opioid-induced hyperalgesia (Bessiere et al., 2007; Richebe et al., 2005). Accordingly, our data imply that the adaptive mechanisms that underlie the development of a notably robust hyperthermic overshoot during N 2 O administration do not depend on intact NMDA signaling. "
ABSTRACT: Changes in typical whole-animal dependent variables following drug administration represent an integral of the drug's pharmacological effect, the individual's autonomic and behavioral responses to the resulting disturbance, and many other influences. An archetypical example is core temperature (T(c)), long used for quantifying initial drug sensitivity and tolerance acquisition over repeated drug administrations. Our previous work suggested that rats differing in initial sensitivity to nitrous oxide (N(2)O)-induced hypothermia would exhibit different patterns of tolerance development across N(2)O administrations. Specifically, we hypothesized that rats with an initially insensitive phenotype would subsequently develop regulatory overcompensation that would mediate an allostatic hyperthermic state, whereas rats with an initially sensitive phenotype would subsequently compensate to a homeostatic normothermic state. To preclude confounding due to handling and invasive procedures, a valid test of this prediction required non-invasive thermal measurements via implanted telemetric temperature sensors, combined direct and indirect calorimetry, and automated drug delivery to enable repeatable steady-state dosing. We screened 237 adult rats for initial sensitivity to 70% N(2)O-induced hypothermia. Thirty highly sensitive rats that exhibited marked hypothermia when screened and 30 highly insensitive rats that initially exhibited minimal hypothermia were randomized to three groups (n=10 each/group) that received: 1) twelve 90-min exposures to 70% N(2)O using a classical conditioning procedure, 2) twelve 90-min exposures to 70% N(2)O using a random control procedure for conditioning, or 3) a no-drug control group that received custom-made air. Metabolic heat production (via indirect calorimetry), body heat loss (via direct calorimetry) and T(c) (via telemetry) were simultaneously quantified during N(2)O and control gas administrations. Initially insensitive rats rapidly acquired (3(rd) administration) a significant allostatic hyperthermic phenotype during N(2)O administration whereas initially sensitive rats exhibited classical tolerance (normothermia) during N(2)O inhalation in the 4(th) and 5(th) sessions. However, the sensitive rats subsequently acquired the hyperthermic phenotype and became indistinguishable from initially insensitive rats during the 11(th) and 12th N(2)O administrations. The major mechanism for hyperthermia was a brisk increase in metabolic heat production. However, we obtained no evidence for classical conditioning of thermal responses. We conclude that the degree of initial sensitivity to N(2)O-induced hypothermia predicts the temporal pattern of thermal adaptation over repeated N(2)O administrations, but that initially insensitive and sensitive animals eventually converge to similar (and substantial) magnitudes of within-administration hyperthermia mediated by hyper-compensatory heat production.Journal of Thermal Biology 01/2012; 37(1):30-40. DOI:10.1016/j.jtherbio.2011.10.004 · 1.51 Impact Factor
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ABSTRACT: ), propofol (2,5 mg.kg -1 ) y cisatracurio (0,15 mg.kg -1 ). Durante la anestesia, la CEsevo se ajustó para mantener el BIS entre 40 y 60. Posteriormente a la instalación del neumoperitoneo, se inició la administración de óxido nitroso en concentraciones aumentadas de 20%, 40% y 60%. Se comprobaron los parámetros BIS, SEF95%, presión arterial sistólica (PAS), presión arterial diastólica (PAD), presión arterial media (PAM) y frecuencia cardiaca (FC), en los momentos M1 - 5 minutos después neumoperitoneo, M2 - cuando la concentración expirada del N 2 O = 20% (CEN 2 O = 20%); M3 - CEN 2 O = 40%; M4 - CEN2O = 60%.
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ABSTRACT: La survenue d’une douleur postopératoire est une situation qui dépend de facteurs préopératoires, peropératoires et postopératoires précoces. Les facteurs préopératoires sont multiples et se traduisent par une vulnérabilité plus ou moins élevée au développement d’une douleur directement liée à l’agression chirurgicale ainsi qu’à la signification de celle-ci dans un contexte biographique et environnemental déterminé. L’accent a été mis, ces dernières années, sur l’importance de la réduction des influx nociceptifs et la gestion de la douleur postopératoire précoce, pour limiter la probabilité d’une persistance d’une douleur postchirurgicale. Cependant, les facteurs de vulnérabilité préopératoires s’avèrent au moins aussi importants que ceux potentiellement gérables par optimisation de l’analgésie peropératoire et du geste chirurgical. Les données expérimentales vont en effet dans le sens d’une véritable mémorisation d’agressions antérieures, favorisant une hypersensibilité nociceptive ultérieure, phénomène particulièrement évident dans un contexte chirurgical, surtout s’il est posttraumatique ou d’ordre carcinologique, ou mettant en jeu un pronostic fonctionnel. La prise en compte de ces facteurs de vulnérabilité préopératoires incite à développer une véritable stratégie thérapeutique préventive basée sur des médicaments aux propriétés antihyperalgésiques ou à des alternatives non médicamenteuses. The occurrence of chronic postoperative pain depends on multiple factors, before surgery, during surgery and after it. These factors lead to more or less individual vulnerability, directly linked to the surgery itself but also in a given biographic context and determined environment. Recently, emphasis has been put on reducing nociceptive inputs during acute postoperative pain management, to limit the likelihood of chronic postoperative pain. It seems however that surgical vulnerability is as important as pain management for the optimization of surgical analgesia and the quality of the surgical act. Experimental data support the concept of an implicit memory for previous aggression, predisposing to personal nociceptive hypersensitivity, especially in the context of surgery, particularly if it is post-traumatic or carcinologic. Taking these vulnerability factors into account prompts us to develop new antihyperalgesic strategies based on pharmacological and non-pharmacological alternatives used prior to or just after surgery.Douleur et Analgésie 03/2009; 22(1):6-12. DOI:10.1007/s11724-009-0121-z · 0.09 Impact Factor