Effects of radolmidine, a novel alpha2 -adrenergic agonist compared with dexmedetomidine in different pain models in the rat.
BACKGROUND
Intrathecally administered alpha2-adrenoceptor agonists produce effective antinociception, but sedation is an important adverse effect. Radolmidine is a novel alpha2-adrenoceptor agonist with a different pharmacokinetic profile compared with the well-researched dexmedetomidine. This study determined the antinociceptive and sedative effects of radolmidine in different models of acute and chronic pain. Dexmedetomidine and saline served as controls.


METHODS
Male Sprague-Dawley rats were studied in acute pain (tail flick), carrageenan inflammation, and the spinal nerve ligation model of neuropathic pain. Mechanical allodynia was assessed with von Frey filaments, cold allodynia with the acetone test, and thermal hyperalgesia with the paw flick test. Locomotor activity-vigilance was assessed in a dark field. Dexmedetomidine and radolmidine were administered intrathecally in doses of 0.25 microg, 2.5 microg, 5 microg, and 10 microg.


RESULTS
In the tail flick test, radolmidine showed a dose-dependent antinociceptive effect, being equipotent compared with dexmedetomidine. In carrageenan inflammation, intrathecal doses of 2.5 microg or 5 microg of dexmedetomidine/radolmidine produced significant antinociception compared with saline (P < 0.01). The two drugs were equianalgesic. In the neuropathic pain model, an intrathecal dose of 5 microg dexmedetomidine-radolmidine had a significant antiallodynic effect compared with saline (P < 0.01). The two drugs were equipotent. Intrathecal administration of both dexmedetomidine and radolmidine dose dependently decreased spontaneous locomotor acitivity-vigilance, but this effect was significantly smaller after intrathecal administration of radolmidine than after intrathecal dexmedetomidine.


CONCLUSIONS
Radolmidine and dexmedetomidine had equipotent antinociceptive effects in all tests studied. However, radolmidine caused significantly less sedation than dexmedetomidine, probably because of a different pharmacokinetic profile.
Department of Pharmacology and Toxicology, Institute of Biomedicine, University of Helsinki, Helsinki University Hospital, Finland. mei.xu@helsinki.fi
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D000316:Adrenergic alpha-Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D003250:Constriction; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007093:Imidazoles / Q000378:metabolism*; D007189:Indans / Q000378:metabolism*; D007249:Inflammation / Q000188:drug therapy*; D007278:Injections, Spinal; D008297:Male; D008954:Models, Biological; D009043:Motor Activity / Q000187:drug effects*; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013127:Spinal Nerves; D013329:Structure-Activity Relationship
D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D007189:Indans; D020927:Dexmedetomidine; C400294:radolmidine