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Effects of the selective alpha 2-adrenoceptor agonist, medetomidine, on a compound volley of a tibial nerve stimulation-evoked spinal reflex, pain-induced phrenic motor responses and on postoperative neuropathic pain behavior were studied in rats. Medetomidine (0.3 mg/kg) decreased the amplitude of the compound volley recorded from peroneal nerve in response to tibial stimulation in pentobarbital (40 mg/kg) anesthetized rats. Atipamezole, an alpha 2-adrenoceptor antagonist (1.5 mg/kg) fully restored the response when given 60 min after the medetomidine administration. Pain-evoked phrenic motor responses were completely inhibited upon combination anesthesia by pentobarbital (40 mg/kg) and medetomidine (0.3 mg/kg) (PB+M) but not upon plain pentobarbital anesthesia (50 or 60 mg/kg) (PB50,PB60). To study the effect of medetomidine on postoperative neuropathic pain behavior (autotomy), transection of sciatic nerve was done under PB+M, PB50 or PB60 anesthesia. No differences between the groups were found in the postoperative pain behavior during eight-week follow up. The results show that activation of alpha 2-adrenergic receptors by medetomidine under pentobarbital anesthesia mitigates trauma-induced afferent barrage, whereas it does not reduce the subsequent autotomy.

It is well established that alpha 2-adrenoceptor agonists have sedative and antinociceptive properties. In the current behavioral study we tried to find out if the alpha 2-adrenergic sedative and antinociceptive effects can be dissociated. We tested the hypothesis that alpha 2-adrenergic sedation is mediated by the locus coeruleus (LC) and antinociception by spinal alpha 2-adrenoceptors. Also, we addressed the possibility that intracerebral injection of an alpha 2-agonist might produce its antinociceptive effect by an action directly at the spinal cord. Medetomidine, an alpha 2-adrenergic agonist, or atipamezole, an alpha 2-adrenergic antagonist, were microinjected bilaterally into the LC through chronic cannulae in unanesthetized Han-Wistar rats. The effect on locomotor activity (/vigilance), tail-flick and hot-plate response, and on formalin-induced pain behavior was determined. Medetomidine microinjected into the LC (1-10 micrograms/cannula) produced dose-dependently hypolocomotion (/sedation), increase of response latencies in the hot-plate and the tail-flick tests, and a decrease in the formalin-induced pain behavior. Hypolocomotion (/sedation) was obtained at a lower medetomidine dose (1 microgram/cannula) than antinociception (3-10 micrograms/cannula). The lowest medetomidine dose used (1 microgram/cannula), which induced significant hypolocomotion (/sedation), produced either no antinociception (hot-plate and tail-flick tests) or even a slight hyperalgesia (formalin test). The hypolocomotion (/sedation) but not antinociception (tail-flick test) induced by systemic administration of medetomidine (100 micrograms/kg s.c.) could be reversed by atipamezole (10 micrograms/cannula) microinjected into the LC. Only a high systemic dose of atipamezole (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Background: The effects of selective alpha-agonist medetomidine and alpha 2-antagonist atipamezole on gastrointestinal motility were studied., Methods: The passage of intragastrically administered Evans blue in the small bowel of unanesthetized rats was followed, and the stomachs were weighted after killing the rats., Results: Subcutaneous medetomidine, 0.01-0.1 mg/kg, was found to delay small intestinal transit but not gastric emptying, with a maximal effect seen at 0.03 mg/kg. Atipamezole fully reversed the effect of 0.1 mg/kg of medetomidine with a dose of 2.5 mg/kg. Atipamezole alone did not affect small intestinal transit. Subcutaneous morphine, 6 mg/kg, delayed gastric emptying and small intestinal transit, whereas intraperitoneal morphine only delayed gastric emptying. Subcutaneous atipamezole, 0.06 mg/kg, was partially able to reverse the delayed intestinal transit but did not inhibit morphine-induced gastric retention. Subcutaneous atipamezole, 0.06 mg/kg, reversed laparotomy-induced ileus completely., Conclusions: Atipamezole may provide a useful treatment for postlaparotomy ileus.

We studied the effects of atipamezole, an alpha 2-adrenoceptor antagonist, on hypnosis induced by medetomidine, an alpha 2-adrenoceptor agonist (1 mg/kg IP), and pentobarbital (40 mg/kg IP) by testing the righting reflex in the rat. The duration of antinociception was assessed with repeated pinch tests. Medetomidine-induced hypnosis and antinociception were inhibited by atipamezole at doses greater than 0.1 mg/kg. Atipamezole restored the righting reflex at a dose ratio that was 1:10 or more to that of medetomidine used to induce hypnosis. Subcutaneous atipamezole (1.5 mg/kg) increased the duration of hypnosis induced by pentobarbital (40 mg/kg) and pentobarbital + medetomidine (0.3 mg/kg). Hypnosis induced by methohexital (60 mg/kg IP) was also prolonged by atipamezole. The capacity of atipamezole to reverse the effects of medetomidine is also reduced in the presence of barbiturates. Thus, atipamezole should be used only at low doses to reverse a combination anesthesia induced by barbiturates and medetomidine.

The behavioral effects of atipamezole (0.5-4.5 mg/kg), a new and highly selective alpha 2-adrenoceptor antagonist, were studied in four behavioral models: open-field, elevated plus-maze, two compartment exploratory test and forced swimming test. Atipamezole (1.5 and 4.5 mg/kg) produced a dose-dependent suppression of locomotor activity in the open field test. In the two compartment exploratory test, the same doses of atipamezole decreased locomotor activity in a 5 min test but not in a 10 min test. The numbers of transitions between the compartments were not significantly affected by atipamezole. Doses of 0.5-4.5 mg/kg did not significantly change the time spent in the open arms or the total number of arm entries in the plus-maze, and doses of 1.5 and 4.5 mg/kg decreased defecation marginally. Vocalization during the forced swimming test was increased by atipamezole (1.5 mg/kg) but the duration of immobility was not increased over the dose range (0.5-1.5 mg/kg) of atipamezole used. Our results suggest that, in the rat, atipamezole decreases motor activity in the early phase of the exploration of new surroundings. In the doses used, atipamezole may suppress defecation and increase vocalization in rats.

In the pentobarbitone-anesthetized cat, the threshold of the tooth pulp-elicited jaw-opening reflex was elevated in a dose-dependent way (30-100 micrograms/kg, IP) following the administration of medetomidine, an alpha-2-adrenoceptor agonist. This elevation was significantly reduced by atipamezole (1 mg/kg, IP), an alpha-2-adrenoceptor antagonist. The inhibitory interaction between two successive dental stimuli applied to the same tooth (in-field inhibition) was suppressed by a lower dose of medetomidine (30 micrograms/kg) than the threshold elevation to single electrical pulses (55 micrograms/kg). Only the highest dose of medetomidine used (100 micrograms/kg) significantly influenced the temporally facilitated (in-field facilitation) response. In comparison, cocaine, a nonspecific monoaminergic agent, did not produce a significant threshold elevation of the tooth pulp-elicited jaw-opening reflex (1-25 mg/kg, IP). It is concluded that medetomidine, through an action on alpha-2-adrenoceptors, can suppress a predominantly nociceptive trigeminal reflex in anesthetized cats. The threshold evoked by single electric pulses, in-field inhibition, and in-field facilitation display differential sensitivities to medetomidine effects.

The effect of systemic (intravenous) medetomidine, an alpha-2 adrenoceptor agonist, on pain thresholds was studied in healthy human subjects (n = 6). Medetomidine produced a dose-dependent (cumulative doses: 25 and 50 micrograms) sedative effect evaluated by visual analog scale. Also, a dose-dependent decrease of blood pressure but not of heart rate was seen after administration of medetomidine. Pain threshold to electric stimulation of the tooth pulp and cutaneous heat pain threshold were uninfluenced by medetomidine. An index of cutaneous thermal sensitivity to innocuous stimuli, the width of the thermoneutral zone, also was uninfluenced by medetomidine. Medetomidine produced a significant attenuation of the affective-motivational component (unpleasantness) of tourniquet-induced ischemic pain, whereas the sensory-discriminative component (pain magnitude estimate) of the ischemic pain was not attenuated. The results suggest that systemic medetomidine alone at subanesthetic but sedative and hypotensive doses does not significantly influence the intensity and thresholds of experimental pain, whereas the affective-motivational component of pain can be attenuated.

The effect of systemically administered medetomidine, a selective alpha-2-adrenoceptor agonist, was studied by electrophysiological recordings of the peripherally evoked responses of three different types of sensory neuronal populations in the rat: medial thalamic neurons exclusively responding to mechanical cutaneous stimuli at noxious intensities, spinothalamic tract neurons of the spinal cord responding exclusively or differentially to mechanical cutaneous stimuli at noxious intensities, and low-threshold mechanoreceptive spinal dorsal horn neurons with ascending projections. The neuronal effects were compared with the behavioral data obtained in mechanically and thermally induced nociceptive tail reflex tests in intact and spinal rats. A reversal of the antinociceptive effects was attempted by systemically (1.5 mg/kg, i.p.) or intrathecally (25 micrograms) administered atipamezole, a selective alpha-2-adrenoceptor antagonist. Systemically administered medetomidine produced an atipamezole-reversible, dose-dependent suppressive effect on the evoked responses of nociceptive medial thalamic and spinothalamic tract neurons. A lower dose of medetomidine was needed to suppress significantly (half-maximally) evoked responses of the nociceptive medial thalamic neurons (100 micrograms/kg) than those of the nociceptive spinothalamic tract neurons (300 micrograms/kg). The decrease of evoked responses of the nociceptive spinothalamic tract neurons was accompanied by a decrease in spontaneous activity. The responses of the low-threshold mechanoreceptive projection neurons of the spinal cord were not influenced by medetomidine (30-300 micrograms/kg). The reflex studies with a (anesthetic) medetomidine dose of 300 micrograms/kg indicated that in intact and otherwise drug-free rats, medetomidine produced a significant prolongation of the nociceptive reflex response latency to a tail-pinch and heat; these antinociceptive effects of systemic medetomidine were reversed by systemically and intrathecally applied atipamezole. In spinal rats systemically applied medetomidine (300 micrograms/kg) also produced a significant prolongation of the tail-flick latency, which was reversed by systemically applied atipamezole. The results suggest that a high anesthetic dose of systemically applied medetomidine (300 micrograms/kg) can suppress nociceptive sensory neuronal and reflex responses due to spinal segmental mechanisms through an action on alpha-2-adrenoceptors. This spinal effect is selective to responses of nociceptive neurons, and at least partly postsynaptic as indicated by the concomitant decrease in spontaneous activity. At a lower, subanesthetic (but sedative) dose (100 micrograms/kg) the antinociceptive effect of systemically applied medetomidine can be explained by supraspinal alpha-2-adrenergic mechanisms.

Medetomidine, a new alpha 2-adrenoceptor agonist produced dose-dependent (30-100 micrograms/kg i.p.) analgesia in the formalin test in rats, and this effect was reversed by atipamezole (1 mg/kg), a new alpha 2-adrenoceptor antagonist. However, medetomidine at the dose of 100 micrograms/kg did not influence tail flick latencies or latencies of the biting response to mechanical pinch stimuli. Moreover, medetomidine produced sedation and a decrease in locomotor activity. In comparison, the non-sedative monoaminergic agent, cocaine (25 mg/kg), produced highly significant analgesic effects in the formalin and mechanical pain tests. The cocaine effect in the formalin test was not reversed by atipamezole (1 mg/kg). It is concluded that the analgesic effect of medetomidine in the formalin test is due to supraspinal mechanisms related to sedation and is mediated by alpha 2-adrenoceptors. The alpha 2-adrenoceptors are not involved in cocaine-induced anagesia.