In this study, we observed that the repeated administration of a cannabinoid for 21 days augmented the minimum alveolar concentration of isoflurane. This result coincides with those previously reported [21], in which the increase in the minimum alveolar concentration of isoflurane was attributed to an increase in norepinephrine efflux (previously reported by Page et al. [23]) because of the repeated administration of cannabinoids. The present study was not designed to determine the causes of the observed increase in the minimum alveolar concentration of isoflurane. We do not know the minimum time necessary to generate the observed effect. It will also be important to determine whether all varieties of cannabinoids have the same effect on the minimum alveolar concentration. Similarly, it is unknown whether the cannabinoid used in the present study has the same effect on the MAC of sevoflurane and desflurane. It is also important to determine whether the chronic administration of the different cannabinoids also alters the requirements of the different available injectable anesthetic drugs. At the time the minimum alveolar concentration of isoflurane was determined, the cardiovascular parameters and temperature were within the normal range and did not present statistical differences between groups medicated with cannabinoids and morphine. According to the results, morphine decreased the MAC of isoflurane by 26%, which coincides with results previously reported in the literature [17], but the isoflurane-sparing effect of morphine was weaker in rats chronically treated with a cannabinoid (the minimum alveolar concentration of isoflurane was reduced by only 8%). This can be a consequence of increased noradrenergic activity in the central nervous system due to the chronic administration of cannabinoids [24,25]. It is also interesting to note that there are reports of a cross-tolerance effect between opioid and cannabinoid compounds. The administration of Δ9-THC has been observed to induce the tolerance of the analgesic and cardiovascular effects of morphine [26], and the chronic administration of morphine reportedly induces tolerance of the analgesic effects of Δ9-THC [27]. The mechanism by which this effect is generated is complex and remains unclear [28]. The decrease in the effect of morphine, observed as the lowering of the MAC of isoflurane in rats repeatedly medicated with a cannabinoid, could suggest (in MAC terms) a cross-tolerance effect between cannabinoids and morphine. To the best of the authors’ knowledge, it is unknown whether the different opioids available could cause the same effect.

A statistical difference was observed in the heart rates when the groups medicated with dexmedetomidine were compared with their respective controls. The dexmedetomidine generated a marked bradycardia. This effect on heart rate coincides with the already known cardiovascular effects of α2-adrenoceptor agonists [18]. With respect to the other variables, statistically significant differences were not observed between groups. We also observed that the effect of dexmedetomidine on the minimum alveolar concentration of isoflurane was constant in animals medicated in a sustained manner with a cannabinoid. At the doses used, we observed a reduction of 48% in the minimum alveolar concentration in rats without the effect of the cannabinoid and a decrease of 60% in the MAC in rats repeatedly medicated with WIN. These results indicate that the repeated use of a cannabinoid modifies the isoflurane-sparing effect of dexmedetomidine, unlike what happens with morphine, where we observed a decrease. Although the effect of dexmedetomidine on the sparing effect of isoflurane is already known [29], to the best of the authors’ knowledge, this study is the first to report the increased isoflurane-sparing effect of dexmedetomidine in rats medicated for 21 days with a cannabinoid. Dexmedetomidine, an α2-adrenoceptor agonist, is frequently used to control anxiety, produce variable degrees of sedation depending on the dose administered, generate analgesia, and assist in multimodal analgesia techniques in general anesthesia procedures and in the intensive care unit. Sympatholytic drugs decrease central sympathetic activity, the present concentrations of catecholamines [30], and the halothane MAC (by up to 90%) [31]. Therefore, dexmedetomidine lowers the requirements of inhalational anesthetics by processes other than inhibiting noradrenaline in the nervous system; it has been proven that the locus coeruleus is not the only place where α2-adrenoceptor agonists exercise their mechanisms of action [32]. It is important to determine how the constant administration of a synthetic cannabinoid favors the effect of dexmedetomidine on the requirements of inhalational anesthetics. Unfortunately, our study did not allow us to determine this mechanism. We do not know whether all available α2-adrenoceptor agonists have the same effect. Therefore, it is important to consider the possibility of modifying the anesthetic requirements of individuals who consume or are treated with cannabinoids. These patients may present different responses to the usual doses of morphine and dexmedetomidine during inhalation anesthesia. The authors think it is essential to understand the effects of continuous cannabinoid administration on the requirements of inhalation anesthetics for patients administered general anesthesia and those administered morphine and dexmedetomidine. We feel that it is important to study the various effects that the chronic consumption of cannabinoids could have on the processes involved in the anesthetic and analgesic techniques carried out in different animal species, including humans. The results of this study should be interpreted with caution since WIN is a synthetic cannabinoid and may not reflect the effect of consuming natural cannabinoids.