Interleukin-1 mimics the hyperalgesia induced by a factor obtained by macrophage lysis.

1. Lysis of rat thioglycolate-stimulated peritoneal macrophages releases a low molecular weight factor (0.5 less than MW less than 10 kD) into the supernatant.

The blue infarct: a simple method for the quantification of myocardial damage in the rat.

Evans blue dye was injected iv into rats 24 h before left coronary occlusion (CO) and the dye content extracted with formamide was estimated after various time intervals in the 1) right ventricle, 2) left ventricle above the ligature and 3) the rest of the left ventricle. There was no difference between portion 1 and 2 but portion 3 showed a progressive increase in dye content (2 to 3 fold) up to 24 h after CO. This result indicates that either the infarcted area possesses collateral circulation or a continuous blood backflow occurred.

Participation of the sympathetic system in acetic acid-induced writhing in mice.

We investigated the participation of a sympathetic component in the abdominal contortions induced by intraperitoneal injection of 0.6% acetic acid in the mouse. The beta blocker propranolol (4 mg/kg, sc) caused a small significant (19%) blockade of the contortions but strongly potentiated (greater than 80%) the effect of indomethacin (30% at 5 mg/kg, sc).

A new mechanism of action of dipyrone: blockade of the release of a nociceptive factor from macrophages.

Rat macrophage monolayers pre-treated with endotoxin release into the incubating fluid a factor (MW greater than 10,000) capable of inducing writhing in mice (MNF). This release was inhibited by dipyrone (3.5-35 micrograms/ml) but not by indomethacin (0.

A peripheral sympathetic component in inflammatory hyperalgesia.

Non-steroidal anti-inflammatory drugs (NSAID) only partially inhibit the hyperalgesia in the inflammation induced by carrageenin in the hind rat paw, one of the most frequently used nociceptive tests. We now report that either the guanethidine depletion of peripheral sympathomimetic amines or the treatment with adrenoceptor antagonists (beta-blockers) and a specific dopamine (DA)-1 antagonist (SCH 23390) significantly reduced carrageenin hyperalgesia. These antagonists also abolished the rat paw hyperalgesia induced by several sympathomimetic amines as well as that induced by a selective DA-1 agonist, SKF 38393.

Regional dipyrone nociceptor blockade: a pilot study.

Eighteen of nineteen patients reported relief from chronic pain (40 to 100%, analogue scale) lasting from a few hours to up to two months after single or repeated regional infusion of dipyrone into a limb. A tendency towards increased duration of pain relief was observed after repeated infusions. The present series of observations in man and experiments with rat paw hyperalgesia are consistent with the interpretation that dipyrone blocks a persistent hyperalgesic state which may result from a previous frequent nociceptive stimulation (memory?) rather than an ongoing inflammatory process.

The release of a neutrophil chemotactic factor from peritoneal macrophages by endotoxin: inhibition by glucocorticoids.

Glucocorticoids inhibit the migration of neutrophils induced by endotoxin (E. coli lipopolysaccharide, LPS) in vivo. Macrophage monolayers stimulated by LPS showed a dose-dependent release into the supernatant of a chemotactic factor for neutrophils, MNCF, which was active in vivo and in vitro.

Restoration by levamisole of endotoxin-inhibited neutrophil migration, oedema and increased vascular permeability induced by carrageenin.

Intravenous administration of E. coli lipopolysaccharide (LPS) inhibited the migration of neutrophils into the pleural cavity that occurs following challenge with intrapleural carrageenin. Treatment of animals with levamisole (10 mg/kg i.

Macrophages stimulated with lipopolysaccharide release a selective neutrophil chemotactic factor: an in vivo demonstration.

Intraperitoneal injection of a chemotactic factor released by macrophage monolayers preincubated with endotoxin induced the migration of neutrophils but not of macrophages into the abdominal cavity of rats, whereas injection of carrageenin, thioglycolate or endotoxin stimulated the migration of both types of cells.

Prostaglandins, pain, and inflammation.

The prevention of hyperalgesia by inhibition of prostaglandin synthesis is the most plausible hypothesis on the mechanism of NSAID action. This review also discusses other possibilities of controlling inflammatory hyperalgesia, including the development of peripherally acting opiates. These are obtained by reduction of the opiates' lipophilic properties.

Blockade by antimacrophage serum of the migration of PMN neutrophils into the inflamed peritoneal cavity.

The effect of rat antimacrophage serum (rAMS) was tested on the influence of normal or thioglycollate-stimulated macrophage populations of the rat peritoneal cavity on the migration of polymorphonuclear neutrophils (PMN) induced by carrageenin, heterologous serum (rabbit) and sheep red blood cells. The rAMS used did not cross-react with PMN or lymphocytes nor did it affect circulating white cells, complement levels or lysed PMN present in the inflammatory exudate. It did, however, give a positive immunofluorescence reaction with resident and stimulated macrophages.

Mode of analgesic action of dipyrone: direct antagonism of inflammatory hyperalgesia.

Dipyrone blocked carrageenin-induced oedema and hyperalgesia in a dose-dependent manner. In contrast with indomethacin, paracetamol and acetyl salicylic acid, much lower doses of dipyrone were necessary for blocking hyperalgesia (ED50 = 19 mg/kg, i.p.

Antinociceptive models displaying peripheral opioid activity.

A writhing syndrome was induced in mice by intraperitoneal administration of carbacyclin (1-100 micrograms/kg), a potent stable analogue of prostacyclin. A quaternary opiate agonist and antagonist, N-methyl morphine and N-methyl nalorphine respectively, exhibited potent antinociceptive properties on subcutaneous administration in this model. Naloxone and naltrexone also displayed weak antinociceptive activity in carbacyclin-induced writhing.

History of the development of inhibitors of angiotensin I conversion.

The major steps in the initial development of angiotensin I conversion inhibitors are described, from the discovery of the Bothrops peptides (bradykinin potentiating factor) to the demonstration of the therapeutic potential. It is a history where chance, serendipity and clear scientific reasoning weaved together the work of several scientists. It is also a classical example of drug development for which the initial basic research was made at the university, but the useful product was achieved by industry.

Is methylnalorphinium the prototype of an ideal peripheral analgesic?

Oral methylnalorphine ( methylnalorphinium ) caused a dose-dependent selective inhibition of inflammatory hyperalgesia (measured in the rat by a modified version of the Randall- Selitto test) without affecting the oedema. When subcutaneously injected, repeated doses of morphine for 5 days caused progressive analgesic tolerance. Tolerance was not observed after similar treatment with methylnalorphinium or methylmorphinium .

The peripheral analgesic effect of morphine, codeine, pentazocine and d-propoxyphene.

The prostaglandin hyperalgesia and tail immersion tests were used to evaluate the analgesic action of morphine, codeine, d-propoxyphene and pentazocine following intraperitoneal, intraplantar and intracerebroventricular administration to rats. In the prostaglandin hyperalgesia test, all drugs produced a dose-dependent analgesia by the various routes. The rank order of potency after intraperitoneal administration was morphine (100) greater than d-propoxyphene (4) greater than pentazocine (2) greater than codeine (1).

The analgesic effect of quaternary analogues of morphine and nalorphine.

1. The effects of N-methyl morphine and N-methyl nalorphine were studied on the hyperalgesia induced by prostaglandin E2 in the rat paw. Morphine and N-methyl morphine injected intraperitoneally (2-8 mg/kg) caused a dose-dependent analgesia.

Prostaglandin hyperalgesia, V: a peripheral analgesic receptor for opiates.

Prostaglandin E2 injected in the rat paw causes hyperalgesia which is antagonized by local injections of opiate and opiate antagonists. In the present investigation in rats it is shown that naloxone has an analgesic effect at doses as low as 2 micrograms/site, injected into the rat hind paw. At a dose that has no analgesic effect (1 microgram/site) naloxone antagonized the analgesia produced by either local or systemic administration of morphine.

Local control of inflammatory pain.

The mechanism of the local hyperalgesic action of prostaglandin E2 has been studied using rat paw oedema. Prostaglandin E2 is a metabotropic transmitter, activating adenylate cyclase, either directly or through the release of a stimulatory protein factor. This activation of adenylate-cyclase is blocked, locally, by opiates.

Blockade of the inflammatory effects of platelet-activating factor by cyclo-oxygenase inhibitors.

1. The edematogenic and hyperalgesic effects of synthetic Platelet-Activating Factor (PAF-acether) on the rat paw were investigated. 2.

Prostaglandin hyperalgesia, IV: a metabolic process.

Prostaglandin E2, prostacyclin and Db-cAMP injected into the rat paw induce hyperalgesia. This hyperalgesic effect of the prostaglandins but not of Db-CAMP was blocked by pre-treatment of the animals with cycloheximide. Prostaglandin hyperalgesia thus seems to be dependent on the triggering of some metabolic process which enhances the effects of physical or chemical stimuli.

Peripheral analgesia: mechanism of the analgesic action of aspirin-like drugs and opiate-antagonists.

1 Prostaglandins released by tissue injury sensitize nociceptors and produce hyperalgesia. 2 Aspirin-like drugs inhibit prostaglandins I2 and E2, synthesis, which explains their anti-algic effect. 3 The anti-algic effect of aspirin-like drugs in carrageenin-induced rat paw inflammation may involve a central component.

The fate of circulating biologically active peptides in the lungs.

The factors which regulate the disappearance of endogenous active substances during pulmonary transit are discussed. The presence of hydrolytic enzymes in the cytosol is not the only factor regulating pulmonary metabolism. An uptake-transport process is required to permit access to intracellular enzymes.