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 alpha 2 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 > or = 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 > or = 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.
Meert
T F
TF
Janssen Research Foundation, Department Neuropsychopharmacology, Beerse, Belgium.
De Kock
M
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003000:Clonidine; D004333:Drug Administration Routes; D004357:Drug Synergism; D005283:Fentanyl / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D020926:Medetomidine; D009294:Narcotics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D007093:Imidazoles; D009294:Narcotics; D018341:Receptors, Adrenergic, alpha-2; D003000:Clonidine; D020926:Medetomidine; D005283:Fentanyl