Intraperitoneal (IP) injection of the serine proteinase inhibitor phenylmethylsulfonyl fluoride (PMSF) produced dose-dependent analgesia in Sprague-Dawley rats. AD50 was 2.9 +/- 1.4 (S.E.) mg kg-1, the analgesia was antagonized by naloxone but unaffected by atropine. PMSF significantly enhanced the analgesic effect of beta-endorphin (END) given by intracerebroventricular (ICV) infusion in rats, the enhanced END analgesia was naloxone-reversible. In Swiss-Webster mice the 24-hr LD50 value for PMSF was 215 +/- 55 mg kg-1 IP; autonomic and behavioral responses were similar to those seen in rats with ICV END. These results indicate that systemic PMSF can protect central endorphin(s) from enzymatic destruction. The significant analgesia, low toxicity, naloxone reversibility and minimal anticholinesterase effects suggest the use of PMSF as a parenteral analgesic.

Analgesia↗

PubMedDate not supplied

Specific binding and uptake of opioids in brain slices.

Studies on slices from whole rat brain indicate that the opioid peptide/receptor, but not the opiate drug/receptor, complex is internalized by metabolically-dependent processes. Opiate drugs displace 3H-etorphine from high affinity binding sites with potencies identical to those in brain homogenates. 3H-metenkephalin (ME) binds to a high affinity (IC50 10 nM) and a low affinity (micromolar) site. Opiate drugs and beta-endorphin compete at the high affinity but not at the low affinity binding site for ME. The biological relevance of the low affinity ME-binding site, which like the high affinity site is internalized, remains to be determined. The slice technique should be useful in the characterization of receptor dynamics that may be altered during opiate tolerance and dependence.

Animals↗

PubMedDate not supplied

Climbing behavior permits in vivo assessment of pre- and postsynaptic extrapyramidal dopaminergic function in mice.

The natural tendency of mice to climb has been investigated in this study as an index of extrapyramidal dopaminergic function. Depending on dose, apomorphine reduced (low dose range; presynaptic dopamine receptor agonism) or increased (high dose-range; postsynaptic dopamine receptor agonism) climbing activity with respect to spontaneous basal levels of such activity in Swiss-Webster mice. We report also an increase in apomorphine-induced enhancement of vertical climbing activity in mice withdrawing from the acute effects of cesium chloride. Spontaneous climbing activity in mice could reflect dynamic extrapyramidal motor tone, upon which voluntary motor activity is superimposed and which, in humans, is adversely affected in motor disorders like parkinsonism.

Animals↗

PubMedDate not supplied

Phosphate energy metabolism during domoic acid-induced seizures.

The effect of domoic acid-induced seizure activity on energy metabolism and on brain pH in mice was studied by continuous EEG recording and in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. Mice were divided into ventilated (n = 6) and nonventilated (n = 7) groups. Baseline EEG was 0.1-mV amplitude with frequence of > 30-Hz and of 4-5 Hz. After intraperitoneal (i.p.) administration of domoic acid (6 mg/kg), electrographic spikes appeared at increasing frequency, progressing to high-amplitude (0.1-0.8 mV) continuous seizure activity (status epilepticus). In ventilated mice, the [31P]NMR spectra showed that high-energy phosphate levels and tissue pH did not change after domoic acid administration or during the intervals of spiking or status epilepticus. Nonventilated mice showed periods of EEG suppression accompanied by decreases in the levels of high-energy phosphate metabolites and in pH, corresponding to episodic respiratory suppression during the spiking interval. In all animals, status epilepticus was followed by a marked decrease in EEG amplitude that progressed rapidly to isoelectric silence. [31P]NMR spectra obtained after this were indicative of total energy failure and tissue acidosis. In a separate group of ventilated mice (n = 4), domoic acid-induced status epilepticus was accompanied initially by an increase in mean arterial blood pressure (MAP) that slowly returned to baseline level. Isoelectric silence was accompanied by a decrease in MAP to 75 +/- 8 mm Hg. These experiments suggest that domoic acid-induced seizures are not accompanied by an increase in substrate demand that exceeds supply.

Adenosine Triphosphate↗