ABSTRACT
BACKGROUND: MPV-2426 (radolmidine) is a novel alpha-2-adrenoceptor agonist developed for spinal pain therapy. In the present study we determined the segmental distribution and selectivity of the antinociceptive effect induced by MPV-2426 following i.t. administration in rats. METHODS: The experiments were performed in lightly anesthetized rats with an i.t. catheter for administration of drugs into the lumbar spinal cord level. To determine segmental distribution of antinociception, the withdrawal latency of the tail and forepaw from a hot water bath was measured. To determine selectivity of reflex modulation, the effect of i.t. MPV-2426 on the innocuous H-reflex was determined. RESULTS: In the hot water immersion test MPV-2426 produced a dose-dependent (0.3-3.0 microg) prolongation of tail withdrawal latency whereas the effect on forepaw withdrawal latency was short of significance. Dexmedetomidine, the reference alpha-2-adrenoceptor agonist, produced a significant dose-related prolongation of both the tail and the forepaw withdrawal (0.3 and 1.0 microg). MPV-2426 (1.0 and 3.0 microg) produced no significant change in the amplitude of the H-reflex or M-response induced by electrical stimulation of the tibial nerve, nor any change in the modulation of the H-reflex amplitude induced by conditioning sural nerve stimulation. The antinociception induced by MPV-2426 was completely reversed by atipamezole (1 mg/kg s.c.), an alpha-2-adrenoceptor antagonist. CONCLUSION: MPV-2426 produces a selective and segmentally more restricted antinociceptive effect than dexmedetomidine following i.t. administration. The antinoception induced by MPV-2426 is due to action on spinal alpha-2-adrenoceptors.
Subject(s)
Adrenergic alpha-2 Receptor Agonists , Adrenergic alpha-Agonists/pharmacology , Analgesics/pharmacology , Imidazoles/pharmacology , Indans/pharmacology , Adrenergic alpha-Agonists/administration & dosage , Adrenergic alpha-Antagonists/pharmacology , Analgesics/administration & dosage , Analgesics/antagonists & inhibitors , Animals , Dexmedetomidine/pharmacology , Electrophysiology , H-Reflex/drug effects , Hot Temperature , Imidazoles/administration & dosage , Imidazoles/antagonists & inhibitors , Immersion , Indans/administration & dosage , Indans/antagonists & inhibitors , Injections, Spinal , Male , Pain Measurement , Rats , Rats, WistarABSTRACT
BACKGROUND: MPV-2426 is a novel alpha2-adrenoceptor agonist developed for spinal pain therapy. It has proved to be effective in physiologic and neuropathic conditions. In the current study its effectiveness on mechanical hyperalgesia was assessed in a rat model of postoperative pain. METHODS: Rats with intrathecal catheters were anesthetized with pentobarbital, and a 1-cm incision was made in the plantar aspect of the foot and closed. During postoperative days 1 and 2 the antihyperalgesic effects induced by intrathecal MPV-2426, clonidine, and dexmedetomidine were determined by assessing the hind limb withdrawal threshold to calibrated von Frey hairs applied to the skin of the hind paw adjacent to the wound. RESULTS: MPV-2426 administered into the lumbar spinal cord produced a dose-dependent (0.3-10 microg) attenuation of the mechanical hyperalgesia, and this antihyperalgesic effect was completely reversed by yohimbine (1 mg/kg, subcutaneous), an alpha2-adrenoceptor antagonist. Dexmedetomidine (1-3 microg) produced an equipotent antihyperalgesic effect, whereas the effect of clonidine (1-10 microg) was markedly weaker. MPV-2426 (10 microg in 20 microl) administered adjacent to the wound did not produce any effect. Preoperative treatment with an antihyperalgesic dose of MPV-2426 did not prevent the development of hyperalgesia. CONCLUSIONS: Intrathecal MPV-2426 dose-dependently attenuates postoperative hyperalgesia to mechanical stimulation because of an action on alpha2 adrenoceptors. Its antihyperalgesic action is as effective as that produced by dexmedetomidine and is considerably stronger than that produced by clonidine. However, preoperative treatment with MPV-2426 does not prevent the development of postoperative hyperalgesia.