Pharmacology of pravadoline: a new analgesic agent.

Pravadoline is a new chemical entity with analgesic activity in humans. This report describes the pharmacology of pravadoline and compares the activity of pravadoline with that of two major classes of analgesics, the opioids and the nonsteroidal anti-inflammatory drugs (NSAIDs). Like the NSAIDs, pravadoline inhibited the synthesis of prostaglandins (PGs) in mouse brain both in vitro (IC50, 4.9 microM) and ex vivo (ED50, 20 mg/kg p.o.) and displayed antinociceptive activity in rodents subjected to a variety of chemical, thermal and mechanical nociceptive stimuli. Administration of pravadoline prevented the writhing response induced by i.p. administration of acetylcholine (ED50, 41 mg/kg p.o.) or PGE2 (ED50, 24 mg/kg p.o.) and prolonged the response latency induced by tail immersion in hot water at a temperature of 55 degrees C (minimum effective dose, 100 mg/kg s.c.). In the rat, treatment with pravadoline prevented acetic acid-induced writhing (ED50, 15 mg/kg p.o.), brewer's yeast-induced hyperalgesia (Randall-Selitto test) (minimum effective dose, 1 mg/kg p.o.), the nociceptive response induced by paw flexion in the adjuvant-arthritic rat (ED50, 41 mg/kg p.o.) and bradykinin-induced head and forepaw flexion (ED50, 78 mg/kg, p.o.). The antinociceptive activity of pravadoline cannot be explained by an opioid mechanism, because pravadoline-induced antinociception was not antagonized by naloxone (1 mg/kg s.c.) and pravadoline did not bind to opioid receptors at concentrations up to 10 microM. However, like the opioid analgesics, pravadoline diminished the electrically induced twitch response of mouse vas deferens preparations, but, in contrast to opioids, this action of pravadoline was not attenuated by naloxone. The possibility is discussed that this effect of pravadoline upon isolated tissues may contribute to its antinociceptive activity. In contrast to NSAIDs, pravadoline was more potent ex vivo as an inhibitor of the formation of PGs in brain vs. stomach. In addition, pravadoline failed to produce gastrointestinal lesions when administered p.o. to rats or mice, and did not possess significant anti-inflammatory activity at antinociceptive doses. Also unlike NSAIDs, pravadoline inhibited rat gastrointestinal transit when administered at doses similar to those which were antinociceptive. The overall pharmacologic profile of pravadoline suggests that the compound may be capable of managing more diverse or more severe pain than is achieved by anti-inflammatory analgesics, without producing side effects commonly associated with either the opioid or the nonopioid analgesics.

Fibronectin in acute and chronic inflammation.

Recent evidence suggests that fibronectin (Fn), a high molecular weight glycoprotein, may be used as an indicator protein in rats with adjuvant-induced arthritis. Rocket immunoelectrophoresis, using purified goat anti-rat Fn, provided a specific and sensitive means of measuring plasma Fn in rats during the development of various inflammatory disease states. It was shown that normal rat plasma Fn levels of approximately 400 micrograms/ml double within 24 hours after injection of adjuvant. Plasma Fn levels in this model of chronic systemic inflammatory joint disease were tracked for more than 4 months and remained significantly higher than normal. On the other hand, a carrageenan-induced inflammatory response in the pleural cavity of rats resulted in a large local accumulation of leukocytes, but no change in plasma Fn levels. A carrageenan-induced model of acute inflammation resulted in increased paw swelling within 6 hours and enhanced plasma Fn levels within 24 hours; plasma Fn levels returned to normal within 1 week. Quantitation of plasma Fn levels in the rat may provide a useful biochemical parameter for the study of chronic systemic inflammatory diseases.

The relationship between plasma fibronectin levels and autoimmune disease activity in MRL/l mice.

Plasma fibronectin levels increased significantly over time in MRL/l mice with progressive autoimmune disease. At 100 and 120 days of age both male and female MRL/l mice exhibited significantly higher fibronectin (Fn) levels than the more resistant MRL/l controls. Male mice at early time points had Fn levels no greater than controls due perhaps to the later onset of disease in MRL/l males. In contrast, female MRL/l mice, when compared with MRL/n controls, had higher Fn levels from 40 days of age. The proteinuria in these animals was also above MRL/n controls from the first time point taken (Day 40). In a temporal study with female MRL/l mice, Fn levels peaked at age 120 days and reflected the pattern of the survival curve, indicating that plasma Fn levels have an association with disease activity.

The effect of antiinflammatory drugs on plasma fibronectin.

When rats were injected with Freund's adjuvant to induce arthritis, systemic disease as measured by swelling of the noninjected paw, was paralleled by a 100% rise in plasma fibronectin as measured by electroimmunoassay. When arthritic rats were given daily oral doses of nonsteroidal antiinflammatory drugs (NSAID), swelling of the noninjected rear paw was significantly less than that of the untreated arthritic controls. However, in all cases, plasma fibronectin (Fn) levels remained high in drug treated arthritic rats. Whether the NSAID was aspirin (100 mg/kg), phenylbutazone (10, 30, or 100 mg/kg) or indomethacin (0.3, 1 or 3 mg/kg) the pattern remained the same--reduced paw volume and unchanged high plasma Fn levels. Fn levels also remained unaltered in normal animals treated with drugs alone. Though NSAID diminish inflammation, clinical studies have shown that they do not halt disease progression. Our report shows that NSAID also fail to alter production of high levels of plasma Fn.

Effects of haloperidol and d-amphetamine on in vivo 3H-spiroperiodol binding in the rat forebrain(1).

Specific (3)H-spiroperidol ((3)H-Sp) binding was demonstrated to occur, in vivo, throughout the rat forebrain. The highest concentrations of (3)H-Sp were found in regions known to contain dopamine neuron terminals. Acute and repeated administration of low does of haloperidol decreased in vivo (3)H-Sp in subcortical but not cortical regions. Repeated administration of high does of haloperidol followed by washout periods up to 8 days did not lead to an increase in in vivo (3)H-Sp binding; however, a single dose of d-amphetamine caused substantial increases. Analysis of the alterations induced by haloperidol and d-amphetamine suggest that the dopamine receptor changes configuration upon excessive exposure to agonists or antagonists in such a way as to favor the counterpart ligand.

Syntheses, analgetic activity, and physical dependence capacity of 5-phenyl-6,7-benzomorphan derivatives.

The synthesis, analgetic activity, and physical dependence capacity of a large number of 5-phenyl-6,7-benzomorphan derivatives are described. Observations made during the Stevens' rearrangement of 1-benzyl-1-methyl-delta 3-piperidinium salt derivatives (V) under various conditions are discussed. The absolute configuration of the 9-demethyl series and the 2'-deoxy series is established by comparison of their ORD and CD spectra with those of 49, whose absolute configuration was previously established by X-ray crystallography. A convenient synthesis of 3H-labeled phenols using 3H3PO4 is described, as well as the preparation of 14C-labeled compounds by conventional methods.

Antagonism by mianserin and classical alpha-adrenoceptor blocking drugs of some cardiovascular and behavioral effects of clonidine.

Antagonism of pressor responses to sympathetic outflow stimulation and alpha-adrenoceptor agonists in pithed spontaneously hypertensive rats was used to estimate postsynaptic alpha-adrenoceptor blocking activity of mianserin, phentolamine, phenoxybenzamine, piperoxan and yohimbine. Estimation of presynaptic alpha-adrenoceptor blocking activity of these drugs was obtained by studying their ability to antagonize clonidine-induced suppression of positive chronotropic responses to sympathetic outflow stimulation. In this manner, evidence was obtained that mianserin causes selective presynaptic alpha-adrenoceptor blockade. Mianserin, piperoxan and yohimbine antagonized clonidine-induced avoidance blockade or hypotension in spontaneously hypertensive rats, but methysergide, phenoxybenzamine and phentolamine were ineffective. These results suggest that mianserin may antagonize the central effects of clonidine by blockade of noradrenergic presynaptic or autoreceptors and possibly explain the antidepressant effect of mianserin as due to indirect activation of central noradrenergic neurons.

Evidence for a cholinergic fiber tract connecting the thalamus with the head of the striatum of the rat.

Placement of electrolytic lesions in the zona incerta or parafascicular nucleus of the rat forebrain resulted in a marked reduction of choline acetyltransferase (ChAc) activity in the head of the striatum 2-4 weeks later. Lesions of the habenula did not cause this effect implying that concomitant destruction of the fasciculus retroflexus with the parafascicular nucleus was not responsible for the effects observed. The data suggest that there is a cholinergic fiber tract connection between the parafascicular nucleus of the thalamus and the head of the striatum in the rat forebrain.