N. Zonta

Decreased antinociceptive activity of morphine in rats pretreated intraventricularly with 5,6-dihydroxytryptamine, a long-lasting selective depletor of brain serotonin.

The antinociceptive activity of morphine was measured in rats treated with 5,6-dihydroxytryptamine, through cannulae chronically implanted into both lateral ventricles of the brain.This indoleamine, which induces a selective degeneration of serotoninergic nerve terminals in the central nervous system, markedly decreased the effect of morphine. The possible role of 5-hydroxytryptamine on antinociceptive activity of morphine is discussed.

MODIFICATION OF THE ANTINOCICEPTIVE EFFECT OF MORPHINE BY CENTRALLY ADMINISTERED DIAZEPAM AND MIDAZOLAM

1 Intracerebroventricular administration of diazepam or midazolam decreased the antinociceptive effect of morphine in rats as measured by the ‘tail flick’ method. 2 Midazolam, injected into the periaqueductal grey matter (PAG) antagonized the analgesic effect of morphine. The action of midazolam was partially reversed by bicuculline. 3 These findings support the view that the effect of benzodiazepines on morphine antinociception may be mediated through γ‐aminobutyric acid receptors.

Periaqueductal gray matter involvement in the muscimol-induced decrease of morphine antinociception

SummaryMicroinjections of muscimol, a GABA receptor agonist, into the periaqueductal gray matter (PAG) counteracted the antinociceptive effect of morphine in rats, as measured by the “tail-flick” method. Muscimols effect was partially reversed by bicuculline.

Muscimol antagonism of morphine analgesia in rats.

1 Muscimol, a γ‐aminobutyric acid (GABA) receptor agonist, when injected intraventricularly antagonizes the antinociceptive effect of morphine given either subcutaneously or intraventricularly. The antagonistic effect of muscimol on morphine analgesia appears to be linearly related. 2 This finding provides support for the view that a GABA‐ergic system is involved in morphine analgesia.

Effects of some GABA-mimetic drugs on the antinociceptive activity of morphine and ?-endorphin in rats

SummaryIntracerebroventricular administration of muscimol, a potent GABA-receptor agonist, counteracted the antinociceptive effect of morphine or β-endorphin in rats as measured by the “tail flick” method. Muscimols activity was reversed by bicuculline. Isoguvacine, another GABA agonist, as well as nipecotic acid and guvacine, two inhibitors of neuronal and glial uptake of GABA, also antagonized morphines antinociceptive effect. A role of the central GABA-ergic system in mediating opiate antinociception is proposed.

Effects of diazepam on nociception in rats

SummaryAcute i.p. injection of diazepam (1 mg/kg) resulted in a moderate increase in the tail-flick latency in rats. Tolerance to this diazepam effect developed after 10 days of diazepam treatment (1 mg kg−1 day−1). The benzodiazepine antagonist Ro 15-3505 only partially reversed the effect of diazepam on nociception. Naloxone (5 mg/kg i.p.) failed to affect the effect of diazepam on nociception, while the kappa antagonist MR 2266 fully antagonized the diazepam-induced increase of the tail-flick latency.Diazepam injected intracerebroventricularly (1, 5, 20 μg/rat) did not alter basal nociceptive threshold, however, diazepam injected intrathecally (20 μg/rat) prolonged the tail-flick latency. Furthermore, intracerebroventricular injection of muscimol partially antagonized the i.p. diazepam-induced increase of the tail-flick latency.These results suggest that benzodiazepine receptor sites are partially involved in the effect of diazepam on nociception and indicate that an indirect kappa-opioid-receptor-mediated mechanism may be involved. The anatomical site of diazepam action on tail-flick latency seems to be at the spinal level. Descending axons to the spinal cord from brain areas reached by intracerebroventricular injection of muscimol seem to modulate the effect of diazepam effect on nociception.

The effect of gabaergic agents on opiate analgesia

Summary The present study shows that the intraventricular injection of muscimol (250 ng/ventricle), a potent GABA receptor agonist, strongly antagonized morphine and β-endorphin analgesia. Furthermore, isoguvacine, a compound structurally related to muscimol, and nipecotic acid and guvacine, inhibitors of GABA uptake, administered intraventricularly markedly attenuated the analgesic effect of morphine. These results further substantiate that the GABAergic system is involved in morphine analgesia. A possible mechanism of action is discussed.

Reversal of the effect of centrally-administered diazepam on morphine antinociception by specific (Ro 15-1788 and Ro 15-3505) and non-specific (bicuculline and caffeine) benzodiazepine antagonists

SummaryDiazepam, injected into the lateral ventricles reduced the antinociceptive effect of morphine in rats, as measured by the tail-flick method. Specific antagonists of diazepam (Ro 15-1788 and Ro 15-3505) had no effect themselves but prevented inhibition by diazepam of morphine antinociception. Furthermore, the action of diazepam was partially reversed by intracerebroventricular injection of bicuculline or caffeine. These findings support the view that the depressant effect of diazepam on morphine antinociception is specific and GABAergic in nature and that some actions of diazepam are also mediated via the purinergic system.

Neurotransmitter amino acid variations in striatum of rats exposed to 50 Hz electric fields

Concentration of neurotransmitter amino acids (Tau, Gly, Asp, Glu, Gln, Ala, GABA) were measured in rat striatum following varying exposure (320 to 1408 h) to high intensity (50 Hz) electric fields. Tissue extracts in methanol, after drying, were derivatized with dansyl chloride and the amino acids quantitated by high-pressure liquid chromatography with ultraviolet detection. Short exposures (320 h) to 100 kV/m field induced a decrease in almost all tested amino acids. Longer exposure times (640 h) to 25 and 100 kV/m were only associated with a decrease in Tau. A further increase of the exposure time (1240 and 1408 h) both at 25 and 180 kV/m were mainly associated with a reduction of the amino acid levels. It is concluded that electric fields in the range 20-180 kV/m generate bimodal variations in neurotransmitter amino acids with troughs at very short and longer exposure times, independent from the field strength.

Purine involvement in morphine antinociception.

1 The effects of a series of adenosine derivatives on morphine antinoceptive effect were investigated in rats by the ‘tail‐flick’ method. 2 2‐Chloroadenosine (CADO) and L‐N6‐phenylisopropyladenosine (L‐PIA), given intraperitoneally, caused decreased morphine antinociception. 3 Intracerebroventricular injections of CADO, L‐PIA and 5′‐N‐ethylcarboxamide adenosine (NECA), but not of 2′‐deoxyadenosine, antagonized morphine antinociception. 4 The effects of both central and peripheral injections of CADO and L‐PIA on morphine antinociception were partially reversed by caffeine. 5 Intracerebroventricular injection of dibutyryl‐cyclic 3′,5′ adenosine monophosphate (db cyclic AMP) had no effect on morphine antinociception. 6 These data indicate that adenosine plays a role in morphine‐induced antinociception. The results are discussed in terms of postulated effects of adenosine derivatives on adenylate cyclase.