Potentiation of the Analgesic Properties of Fentanyl-like Opioids With Alpha(2)-adrenoceptor Agonists in Rats

Background: Data on the analgesic properties of alpha(2) agonists and their interactions with opioids are conflicting. Experiments were conducted in rats to evaluate whether various available alpha(2) agonists can potentiate the analgesic properties of opioids and to determine the route of administration needed for optimal interaction. Methods: The tail-withdrawal reaction test was used as an analgesia assay. In separate experiments, the interactions between systemic (subcutaneous, intravenous, and intraperitoneal) and spinally (epidural and intrathecal) administered a, agonists and opioids were evaluated. The antagonism of medetomidine plus fentanyl with naloxone and/or idazoxan also was studied. Results: All alpha(2) agonists tested, when injected subcutaneously with fentanyl, potentiated the opioid-induced analgesia. In terms of a reduction of the amount of fentanyl needed to produce a deep surgical analgesia (tail-withdrawal reaction latency greater than or equal to 10 s) over more than 2 h, the relative order of potency of the alpha(2) agonists tested was: medetomidine > dexmedetomidine > xylazine > clonidine > detomidine. For some of these alpha(2) agonists there was a biphasic effect; at the larger doses tested, a reduction in the fentanyl potentiation was present. The potentiation of the opioid activity with alpha(2) agonists was also demonstrated in terms of a longer duration of analgesia after combined treatment with fixed doses of opioids. The interaction between the alpha(2) agonists and the opioids remained present when a more profound criterion of analgesia (tail-withdrawal reaction latency greater than or equal to 30 s) was used. Furthermore, the interactions between the alpha(2) agonists tested and fentanyl or sufentanil appeared to be independent of the route of administration. Potentiations were observed after simultaneous subcutaneous injections of both groups of compounds, after the combination of intraperitoneal (alpha(2) agonist) plus subcutaneous (opioid), intravenous (alpha(2) agonist) plus epidural (opioid) and simultaneous epidural or intrathecal administrations. With regard to antagonism of the analgesic activity of combined treatment with alpha(2) agonists plus opioids, naloxone provided total antagonism, whereas the alpha(2) antagonist idazoxan overcame only the alpha(2) agonist-induced potentiation of fentanyl. Conclusions: The tested alpha(2) agonists can potentiate the analgesic properties of opioids, but they have no intrinsic antinociceptive effects on spinal reflexes on their own. The potentiating activities of the alpha(2) agonists could be measured both in terms of a reduction of the amount of opioid needed to reach a particular level of analgesia and in terms of a longer duration of analgesia with a fixed dose of the opioid. The potentiations were observed with various alpha(2) agonists and opioids and appeared independent of the routes of administration

Adrenalectomy protects ethanol-withdrawn rats from harmine-induced tremor

A growing number of studies have implicated the hypothalamic-pituitary-adrenal (HPA) axis in acute and chronic alcoholization and in ethanol withdrawal. In order to study the ethanol/HPA axis interaction during alcohol withdrawal. we performed experiments using adrenalectomized (ADX) male rats alcoholized by a chronic pulmonary alcoholization procedure. Eight hours after the 3 weeks of the alcoholization procedure. the rats were evaluated for a tremor activity. In order to reduce the great variability of the withdrawal tremors. we estimated the supersensitivity of the withdrawn rats to the tremorogenic compound harmine. We also studied the effect of a hydrocortisone treatment given in the drinking bottle during the alcoholization procedure on the harmine-induced tremors of ADX and sham rats. Alcohol withdrawal resulted in increased tremor response to 10 me/kg harmine, and a protective effect of adrenalectomy on this effect was observed. Hydrocortisone administration to ADX or sham rats did not affect the tremor profile of the alcohol withdrawn rats