Baptiste Bessiere

Nitrous oxide (N2O) prevents latent pain sensitization and long-term anxiety-like behavior in pain and opioid-experienced rats

Improving rehabilitation after a severe tissue injury does not only require a reduction in pain, but also requires alleviation of negative affects, particularly anxiety. Although opioids remain unsurpassed analgesics to relieve moderate to severe pain, it has been shown that they also induce latent pain sensitization leading to long-lasting hyperalgesia via N-methyl-D-aspartate-(NMDA)-dependent pronociceptive systems. The present study evaluated the ability of nitrous oxide (N2O), a gas with NMDA antagonist properties, to prevent latent pain sensitization and long-term anxiety-like behavior (ALB) in rats with pain and opioid experiences. On D0, the pro-inflammatory drug carrageenan was injected in one hind paw of rats treated with fentanyl (4x100 microg/kg subcutaneously). Nociceptive threshold was evaluated with the paw pressure vocalization test. Rats were re-exposed to carrageenan or exposed to repeated non-nociceptive environmental stress (NNES) 2-3 weeks later. Rats were also challenged in the elevated plus-maze 2 weeks after fentanyl administration for evaluating ALB. The preventive effects of a single 4 h 50/50% N2O-O2 exposure performed on D0 was evaluated. Fifty percent N2O strongly reduced hyperalgesia induced by a first inflammation and its enhancement by fentanyl, and prevented exaggerated hyperalgesia induced by second inflammatory pain or NNES. Moreover, we provide first evidence that a high fentanyl dose induces long-term ALB 2 weeks after its administration. When associated with fentanyl, 50% N2O prevented such long-term ALB. These results suggest that a single exposure to N2O could improve post-injury pain management and facilitate rehabilitation especially when potent analgesics as opioids have to be used.

A Single Nitrous Oxide (N2O) Exposure Leads to Persistent Alleviation of Neuropathic Pain in Rats

UNLABELLEDnUsing the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N2O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10 degrees C water bath. A single 50% N2O exposure for 1 hour, 15 minutes not only induced potent anti-nociception during N2O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N2O exposure. A preadministration of naltrexone, which markedly reduced acute N2O-induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N2O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N2O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N2O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner.nnnPERSPECTIVEnBecause a single 50% N2O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N2O effects in patients with neuropathic pain. The ability of N2O to potentiate analgesic effects of other drugs also must be evaluated.

A high-dose of fentanyl induced delayed anxiety-like behavior in rats. Prevention by a NMDA receptor antagonist and nitrous oxide (N2O)

Postoperative negative affects such as anxiety need to be better understood and treated to improve patient recovery. The present study evaluates the effect of a single exposure to a high-dose of opioid (4×100 μg/kg fentanyl injections in 15 min intervals resulting in a total dose of 400 μg/kg), as used for surgery in humans, on anxiety-like behavior (ALB) in rats. First, the level of anxiety was evaluated 24-h after a high-dose of fentanyl using an elevated plus-maze apparatus. Second, the preventive effect of BN2572, a N-methyl-D-aspartate receptor (NMDA-R) antagonist, and 50% nitrous oxide (N(2)O), a gas with NMDA-R antagonist properties, was assessed. A significant increase in ALB was observed in fentanyl-treated rats. Interestingly, fentanyl-induced ALB was prevented by BN2572, suggesting a NMDA-dependant pathway. Fentanyl-induced ALB was also prevented by a single 50% N(2)O exposure. The present study provides evidence that deleterious outcomes of opioid use, referred to as post-opioid syndrome, include not only pain hypersensitivity as previously described, but also negative affects such as anxiety. Since N(2)O prevents elements of this post-opioid syndrome, we speculate that N(2)O could be a good therapeutic agent to facilitate postoperative rehabilitation.

Xenon prevents inflammation-induced delayed pain hypersensitivity in rats

Rats received an intraplantar carrageenan injection for inducing hind paw inflammation. After 1 h 45 min, they were exposed to medical air (air group), xenon 25% (Xe-25 group) or 50% (Xe-50 group) for 1 h 45 min. Mechanical nociceptive threshold was evaluated on experimental day and once daily for 1 week. Beyond the well-known antinociceptive effect of xenon, the delayed hyperalgesia observed for 4 days after carrageenan injection was strongly reduced in Xe-25 group and totally suppressed in Xe-50 group on the inflamed hind paw. Moreover, delayed hyperalgesia on the noninflamed hind paw was totally suppressed for both the xenon concentrations. These results show that xenon, beyond its antinociceptive effects, may be a fruitful therapeutic strategy to limit the development of pain sensitization after tissue injury.

The Effects of Xenon and Nitrous Oxide Gases on Alcohol Relapse

BACKGROUNDnIn recent years, the glutamate theory of alcoholism has emerged as a major theory in the addiction research field and N-methyl-d-aspartate (NMDA) receptors have been shown to play a major role in alcohol craving and relapse. The NMDA receptors are considered as the primary side of action of the anesthetic gases xenon (Xe) and nitrous oxide (N2 O). Despite the rapid on/off kinetics of these gases on the NMDA receptor, a brief gas exposure can induce an analgesic or antireward effect lasting several days. The aim of this study was to examine the effect of both Xe and N2 O on alcohol-seeking and relapse-like drinking behavior (measured as the alcohol deprivation effect) in Wistar rats.nnnMETHODSnWe used 2 standard procedures-the alcohol deprivation model with repeated deprivation phases and the cue-induced reinstatement model of alcohol seeking-to study the effect of 2 brief gas exposures of either Xe, N2 O, or control gas on relapse-like drinking and alcohol-seeking behavior.nnnRESULTSnHere, we show that exposure to Xe during the last 24xa0hours of abstinence produced a trend toward reduced ethanol intake during the first alcohol re-exposure days. In addition, Xe gas exposure significantly decreased the cue-induced reinstatement of alcohol-seeking behavior. N2 O had no effect on either behavior.nnnCONCLUSIONSnXe reduces alcohol-seeking behavior in rats and may therefore also interfere with craving in human alcoholics.

Inhaling xenon ameliorates l-dopa-induced dyskinesia in experimental parkinsonism: Xenon Ameliorates Dyskinesia

Parkinsons disease motor symptoms are treated with levodopa, but long‐term treatment leads to disabling dyskinesia. Altered synaptic transmission and maladaptive plasticity of corticostriatal glutamatergic projections play a critical role in the pathophysiology of dyskinesia. Because the noble gas xenon inhibits excitatory glutamatergic signaling, primarily through allosteric antagonism of the N‐methyl‐d‐aspartate receptors, we aimed to test its putative antidyskinetic capabilities. We first studied the direct effect of xenon gas exposure on corticostriatal plasticity in a murine model of levodopa‐induced dyskinesia We then studied the impact of xenon inhalation on behavioral dyskinetic manifestations in the gold‐standard rat and primate models of PD and levodopa‐induced dyskinesia. Last, we studied the effect of xenon inhalation on axial gait and posture deficits in a primate model of PD with levodopa‐induced dyskinesia. This study shows that xenon gas exposure (1) normalized synaptic transmission and reversed maladaptive plasticity of corticostriatal glutamatergic projections associated with levodopa‐induced dyskinesia, (2) ameliorated dyskinesia in rat and nonhuman primate models of PD and dyskinesia, and (3) improved gait performance in a nonhuman primate model of PD. These results pave the way for clinical testing of this unconventional but safe approach.