Pharmacological profile of intrathecal fadolmidine, a alpha2-adrenoceptor agonist, in rodent models.
The present experiments compared the peripheral and central pharmacological effects of three alpha(2)-adrenoceptor agonists: fadolmidine, clonidine, and dexmedetomidine after single intrathecal bolus injections at analgesic dose level in rats. Effects on mydriasis and cardiovascular functions were studied in anaesthetised rats, the effects on sedation/motor performance, body temperature, and gastrointestinal motility were evaluated in conscious rats, and also the effects on brain biogenic amines were studied. All compounds caused dose-dependent mydriasis, a decrease in blood pressure and heart rate, sedation, hypothermia, and inhibition of gastrointestinal transit, but in contrast to the analgesic effects, dexmedetomidine and clonidine were much more potent than fadolmidine. In accordance with the other systemic effects, dexmedetomidine and clonidine, but not fadolmidine, reduced the turnover of the monoamine neurotransmitters, noradrenaline and serotonin, in brain at the analgesic dose. The difference in the systemic effect profile between fadolmidine and clonidine or dexmedetomidine is most probably explained by differences in their ability to spread from the site of administration at the lumbar level into the periphery and/or the brain and further the concentrations of the compounds in the side of action. These results supports that intrathecally administered fadolmidine could have potential to be used as an analgesic agent with less subraspinal or spinal adverse effects at analgesic doses than dexmedetomidine and clonidine.
Leino
Tiina
T
Orion Corporation, Orion Pharma, R&D, Turku, Finland. tiina.leino@orionpharma.com
Viitamaa
Timo
T
Haapalinna
Antti
A
Lehtimäki
Jyrki
J
Virtanen
Raimo
R
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003000:Clonidine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005769:Gastrointestinal Motility / Q000187:drug effects; D007093:Imidazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007189:Indans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007278:Injections, Spinal; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism
D058647:Adrenergic alpha-2 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007189:Indans; D012701:Serotonin; D020927:Dexmedetomidine; D003000:Clonidine; C400294:radolmidine; D009638:Norepinephrine