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Biomedical subjects

A Cowan

Publications and source records attributed to A Cowan.

At least 109 records · Page 6Linked to original sources
PubMed1982

The affinity of morphine for its pharmacologic receptor in vivo.

Morphine receptor affinity, an important constant in the classification of opiate receptors, has not yet been determined by a pharmacologic method. In the present study, we used a standard pharmacologic procedure, that of partial receptor occlusion, to make this determination in the rat utilizing the hot water (55 degrees C) tail flick test. The occluding compound was buprenorphine, a new narcotic antagonist analgesic that can bind to opiate receptors in an irreversible manner. When buprenorphine was given to rats in doses of 0.30 and 0.60 mg/kg (s.c.), 30 min before morphine (20-320 mg/kg s.c.) and 60 min before testing, it produced the theoretically predicted alterations in the morphine dose-response relation that are indicative of partial receptor blockade. The morphine receptor apparent dissociation constant (reciprocal of affinity) was calculated to be 1.7 X 10-6 M. This value is greater than those previously obtained in radiolabeled binding studies which have ranged from 3 to 27 X 10-9 M in the absence of sodium chloride to 1 to 5 X 10-7 M in the presence of sodium chloride. Used in this way, buprenorphine may be a valuable tool in the determination of apparent dissociation constants for other narcotic agonists.

Animals↗
PubMed1981

Opiate-like electroencephalographic and behavioral effects of electroconvulsive shock in rats.

Rats were studied (a) after a single transauricular electroshock (acute ECS) and (b) following 10 consecutive once-daily shocks (chronic ECS). ECS produced a generalized convulsion marked by a polyspike EEG seizure. The seizure was followed by a period of postictal depression (PID) characterized by EEG high-voltage synchrony, EMG quietening, and an associated stuporous behavior in the rat. Acute ECS produced a maximal of 33 +/- 8 (S.E.) percent above control in the EEG voltage output during postictus, with the PID lasting 2680 +/- 658 sec. Chronic ECS resulted in a significant enhancement of these acute responses. Pretreating rats with naloxone (0.3-10 mg/kg s.c.) antagonized the postictal effects of acute ECS, but not of chronic ECS. These naloxone-sensitive postictal EEG and behavioral changes appear to reflect a release of endogenous opioid peptides during ictus, a finding consistent with the hypothesis that electroshock activates opioid systems.

Animals↗
PubMed1981

Time course of antagonism of morphine antinociception by intracerebroventricularly administered naloxone in the rat.

The kinetic profile and half-life of naloxone were studied for possible use in determination of pA2 and KB in vivo. Rats were given morphine subcutaneously and after 15 min naloxone or saline, intracerebroventricularly. A further 15 min later, and at 15 min intervals up to 135 min after morphine, the animals were tested for analgesia in the tail flick test. The dose-response curves of the naloxone group were shifted to the right of those for the saline group. The amount of displacement decreased with time, indicative of the disappearance of naloxone. The graph of log (dose ratio-1) vs. time was linear with negative slope, in agreement with the time-dependent form of the equation for competitive antagonism. From this slope, the half-life of naloxone was calculated to be 13.3 min. These results demonstrate that the time-dependent method is useful in obtaining the kinetics of centrally acting opiate antagonists.

Analgesia↗
PubMed1981

A comparison of the anticonvulsant effects of two systemically active enkephalin analogues in rats.

FK-33,824 (Tyr-D-Ala-Gly-MePhe-Met(O)-ol) and metkephamid (Tyr-D-Ala-Gly-Phe-N(Me)Met-CONH2; LY 127623) are two parenterally active synthetic analogues of the endogenous morphinomimetic pentapeptide, [Met5]-enkephalin. Acute s.c. administration of each analogue raised the seizure threshold in a dose-related manner in rats challenged with flurothyl, a volatile convulsant. The anticonvulsant action was antagonized by a low dose of naloxone (0.10 mg/kg s.c.). FK-33,824 and metkephamid can therefore be classified with typical mu-receptor agonists such as morphine and etorphine in this procedure.

Animals↗
PubMed1981

Use of programmable protocol timer and data logger in the monitoring of animal behavior.

The quantitative assessment of animal behavior by continuous or intermittent observation often requires much time and intense concentration. We have developed an accurate and convenient system which allows one observer to monitor up to four animals and record two types of behavior simultaneously. The system uses an inexpensive portable microcomputer including keyboard, video monitor, and cassette recorder. A program written in BASIC generates timed visible and audible cues, and tabulated data entered through the keyboard. The total number of occurrences of a particular behavior (e.g., "wet dog" shakes) and the frequency of a second behavior (e.g., grooming) may be measured. Frequency data, bases on intermittent observations, is processed for histogram display. The results may be copied from the video display or recorded on tape for further statistical analysis. The system has provided a convenient way to time experiments and collect data on drug-induced behavior in over 800 rats.

Animals↗
PubMed1981

RX 336-M, a new chemical tool in the analysis of the quasi-morphine withdrawal syndrome.

RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) and four other chemically-diverse agents--AG-3-5 (1-[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), Sgd 8473 (alpha-[4-chlorobenzylideneamino)-oxy]-isobutyric acid), thyrotropin releasing hormone (TRH), and sodium valproate--each induce signs of withdrawal, most notably 'wet-dog' shaking, after acute i.p. administration in drug-naive rats. They are therefore additions to a recently recognized and, as yet, ill-defined class of behaviorally active compounds. The pharmacological baselines that link these disparate agents together have been studied in the present work, using 'wet-dog' shaking as the behavioral measure and RX 336-M as the reference shake-inducing compound. Peripheral administration of clonidine, haloperidol, d-lysergic acid diethylamide, or morphine suppressed chemically induced shaking: naloxone had no marked effect. Reverse tolerance was associated with TRH-induced shaking whereas tolerance occurred with the other four compounds. Cross-tolerance interactions were asymmetrical. Thus, rats rendered tolerant to RX 336-M were cross-tolerant to AG-3-5, TRH, and sodium valproate but not to Sgd 8473; in contrast, RX 336-M-induced shaking was only significantly reduced in rats made tolerant to Sgd 8473. In view of the unidirectional nature of the cross-tolerance relationships studied, it is concluded that AG-3-5, Sgd 8473, sodium valproate, and TRH initiate 'wet-dog' shaking through neural substrates that differ from the one(s) associated with RX 336-M. Nevertheless, all five compounds may eventually trigger a common shake-inducing mechanism.

Animals↗
PubMed1980

Pupillary effects of leucine and methionine enkephalin in rats after intraperitoneal administration.

Changes in pupil size after peripheral administration of met-enkephalin, leu-enkephalin, or morphine were studied in the rat. With a simple pupillographic technique, the pupil diameter of male, S.D. rats (250--300 g) was measured by a series of photographs taken every 60 sec for at least 45 min after the last drug injection. Morphine (8 mg/kg, SC) caused mydriasis characterized by rapid and marked fluctuations of pupil size. Mydriasis also occurred after leu-enkephalin (5 and 10 mg/kg, IP) and met-enkephalin (20 mg/kg, IP) Both peptides induced morphine-like fluctuations. When given 15 min after morphine, leu-enkephalin (5 and 10 mg/kg) increased the mydriatic effect of morphine from 172 percent of control to 224 and 272 percent, respectively. Met-enkephalin (20 mg/kg, but not 10 mg/kg) also enhanced the mydriatic response of morphine, to 244 percent of control. These interactions appear to represent simple addition rather than potentiation. The effects of both peptides were reversed by naloxone (1 mg/kg, SC), suggesting an opiate receptor interaction for the pupillary effect of the enkephalins. The rat pupil thus provides one of the few in vivo models permitting quantification of enkephalin action after parenteral administration.

Animals↗
PubMed1979

Classification of opioids on the basis of change in seizure threshold in rats.

Twenty opioids have been subdivided into four classes by using flurothyl-induced seizures in rats to measure dose-response relationships, stereospecificity, naloxone sensitivity, and tolerance-cross-tolerance. The data support current theories of multiple opiate receptor types. Since the receptors involved mediate effects that are antagonized, enhanced, or unaffected by naloxone, the model is uniquely suitable for detecting novel narcotic antagonists that can then be used to differentiate opiate receptors in other systems.

Animals↗