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Biomedical subjects

A Cowan

Publications and source records attributed to A Cowan.

At least 91 records · Page 5Linked to original sources
PubMed1984

Pituitary-adrenal mediation of bombesin-induced inhibition of gastrointestinal transit in rats.

Centrally administered bombesin (0.1-3.5 micrograms, i.c.v.) inhibits gastrointestinal transit of a charcoal meal in a dose-related manner in rats. The roles of pituitary and adrenal glands in the mediation of this effect were assessed. The inhibition of gastrointestinal transit associated with bombesin (0.5 microgram, i.c.v.) was prevented by either hypophysectomy or adrenalectomy. Bombesin-induced inhibition of gastrointestinal transit is therefore mediated through the pituitary-adrenal axis. This is in contrast to bombesin-induced scratching and inhibition of gastric acid secretion which are not markedly influenced by either hypophysectomy or adrenalectomy.

Animals↗
PubMed1984

In vivo evidence for benzomorphan-selective receptors in rats.

The scratching caused by a standard, submaximal dose of bombesin (0.10 microgram i.c.v.) in rats is antagonized in a stereospecific and dose-related manner by systemically (but not centrally) administered benzomorphan analgesics; other commonly used opioids and opioid peptides are ineffective at behaviorally nondepressent doses. Naloxone attenuates the antibombesin effect of ethylketocyclazocine in a stereospecific, potent and dose-related manner. Tolerance develops to the inhibitory action of ethylketocyclazocine (and phenazocine). Multiple injections of morphine do not influence the ability of ethylketocyclazocine or of phenazocine to antagonize bombesin. Furthermore, when mu opiate receptors are occluded by buprenorphine, ethylketocyclazocine and phenazocine can still antagonize bombesin-induced scratching. Benzomorphan-selective binding sites have previously been postulated; we suggest that this test provides evidence of such sites in vivo. The model affords a simple, yet novel, behavioral endpoint that can be used when defining the pharmacological profile of new benzomorphans and their antagonists.

Analgesics, Opioid↗
PubMed1983

Intrathecal bombesin in rats: effects on behaviour and gastrointestinal transit.

When bombesin is given intracerebroventricularly to rats, it is known to cause excessive scratching and inhibit gastrointestinal transit. We have administered bombesin via a permanent indwelling cannula into the subarachnoid space of the lumbar spinal cord of rats. By this route, bombesin elicited immediate excessive scratching and rapidly inhibited passage of a charcoal meal along the gastrointestinal tract. The A50 values for these effects were 0.004 (0.001-0.018) micrograms/rat and 0.34 (0.22-0.55) micrograms/rat, respectively. Bombesin-induced scratching and inhibition of transit are therefore mediated at spinal, as well as supraspinal, levels.

Animals↗
PubMed1983

A species difference in the slowing effect of intrathecal morphine on gastrointestinal transit.

Intrathecal administration of morphine, levorphanol, bremazocine, ethylketocyclazocine or [D-Ser2,Leu5,Thr6]enkephalin to rats, at doses 10-50 times greater than that necessary to elicit analgesia in the tail flick test, had no marked effect on gastrointestinal transit as determined by the charcoal meal test. In contrast, intrathecal administration of various doses of morphine to mice significantly antagonized transit (A50 (that dose which inhibited transit to 50% of controls) = 14.7 (0.71-2.89) micrograms/mouse). These results suggest (1) a lack of involvement of opioid sensitive spinal structures in the control of gastrointestinal transit in rats, and (2) a species difference in the slowing effect of intrathecal morphine on gastrointestinal transit.

Animals↗
PubMed1983

Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration.

The mu agonist, morphine, and the prototype kappa agonists, ketocyclazocine and ethylketocyclazocine (EK), were studied for their effects on gastrointestinal transit. Following s.c. administration, both morphine (0.3-3 mg/kg) and ketocyclazocine (0.3-10 mg/kg) antagonized transit of an opaque marker through the small intestines of mice. Morphine (0.1-1 microgram) was also effective after intracerebroventricular (icv) administration in mice whereas ketocyclazocine (0.3-30 micrograms) was not. Similarly, while both morphine (0.3-5 mg/kg) and EK (0.6-10 mg/kg) slowed transit after s.c. injection to rats, only morphine (1-10 micrograms), but not EK (0.3-300 micrograms), was active following icv administration. Icv infusion of the mu benzomorphan, phenazocine (10-100 micrograms), slowed transit in a dose-related manner. These results indicate that there may be an anatomically distinct distribution of receptors for benzomorphan kappa agonists in both the mouse and rat, with these opiate receptors not being located near the lateral cerebral ventricles. The difference in efficacy between morphine and ketazocines in slowing gastrointestinal transit after icv administration to rodents suggests that (a) inactivity in this endpoint is a characteristic of benzomorphan kappa compounds and (b) the model may serve as a useful screen when establishing in vivo profiles of kappa agonists in mice and rats.

Animals↗
PubMed1983

ACTH-(1-24) and RX 336-M induce excessive grooming in rats through different mechanisms.

ACTH-(1-24) (0.03-6 micrograms i.c.v.) and RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) (1.5-6 mg/kg i.p.) induce dose-related excessive grooming and 'wet-dog' shaking in rats. In the present study, the grooming associated with these compounds was compared and analyzed pharmacologically. Grooming caused by RX 336-M and by ACTH-(1-24) was antagonized when rats were pretreated with comparable doses of morphine (0.5-4 mg/kg s.c.), however, only ACTH-(1-24)-induced grooming was attenuated by naloxone (1 and 10 mg/kg s.c.). ICI 154,129 (N,N-bisallyl-Tyr-Gly-Gly-psi-(CH2S)-Phe-Leu-OH) (30 mg/kg s.c.), a selective delta-opiate receptor antagonist, was ineffective against both ACTH-(1-24) and RX 336-M. Although haloperidol is known to antagonize grooming elicited by ACTH-(1-24) (e.g., Wiegant et al., 1977, European J. Pharmacol. 41, 343), even a high dose of this neuroleptic agent (5 mg/kg s.c.) only partially attenuated grooming caused by RX 336-M. Tolerance developed to the grooming elicited by RX 336-M, and by ACTH-(1-24), but there was no cross-tolerance. Both agents were active in genetically hypotrichotic rats; and, again in such animals, even after numbing the area caudal to the shoulders with lidocaine. Given the divergent results with naloxone, and, possibly, with haloperidol, and the lack of cross-tolerance, we conclude that the excessive grooming induced in rats by ACTH-(1-24) and by RX 336-M is mediated by different mechanisms.

Adrenocorticotropic Hormone↗
PubMed1983

A selective role for delta-receptors in the regulation of opioid-induced changes in seizure threshold.

In an effort to identify delta-receptor-specific properties for opioid modulation of seizure activity, studies were conducted with ICI 154,129, a putative delta-receptor antagonist, in the rat flurothyl test. Rats were pretreated i.c.v. with ICI 154,129 (50 micrograms) which, at this dose, does not alter normal seizure thresholds. Mean seizure thresholds for control groups (i.c.v. saline) ranged between 323-349 sec. In this test, D-Ala2-D-Leu5 enkephalin (20 micrograms, i.c.v.), metkephamid (40 mg/kg, s.c.), and etorphine (20 micrograms/kg, s.c.) raised seizure thresholds by 117, 128, and 140% of control, respectively. Meperidine (25 mg/kg, s.c.) lowered seizure thresholds by 14% less than control. Pretreatment with ICI 154,129 failed to antagonize the proconvulsant action of meperidine or the anticonvulsant and behavioral depressant actions of etorphine. The increases in seizure threshold produced by DADL and metkephamid (two delta-directed ligands) were significantly attenuated by ICI 154,129. However, the DADL-induced wet-shakes, rigid immobility, and behavioral depression were insensitive to ICI 154,129. These data indicate that ICI 154,129 possesses delta-receptor antagonistic properties in this in vivo model of seizure activity. Furthermore, since only the changes in seizure threshold were antagonized, it may be inferred that opioid-induced behavioral depression and DADLE wet-shakes are not a function of delta-receptor activity.

Animals↗
PubMed1983

An animal model for preclinical screening of systemic antipruritic agents.

Reliable antipruritic agents that can be given systemically are not available at present. This may be due to the lack of animal models for screening such compounds. Bombesin, a tetradecapeptide originally isolated from frog skin, induces dose-related excessive scratching when administered intracerebroventricularly (i.c.v.) to rats. With the help of a microcomputer, we monitored the scratching elicited by a standard, submaximal dose of bombesin (0.10 microgram, i.c.v.). This system provides 1) a sensitive and novel way of assessing drug-induced behavioral depression, and 2) a means of quantifying interactions between bombesin and possible antagonists. Thus, bombesin-induced grooming is antagonized by behaviorally nondepressant doses of methdilazine, trimeprazine, and chlorpromazine but not by morphine, haloperidol, diphenhydramine, hydroxyzine, mepyramine, cimetidine, or cyproheptadine. Methdilazine and trimeprazine are used clinically as antipruritic agents. The model therefore offers a means of evaluating new, systemic antipruritic agents, particularly those which may be active in treating histamine-independent pruritus.

Animals↗
PubMed1982

A comparison of the receptor constants of morphine and ethylketocyclazocine for analgesia and inhibition of gastrointestinal transit in the rat.

The efficacies and dissociation constants of proposed mu and kappa receptor agonists (morphine and ethylketocyclazocine, respectively) were compared using the method of partial irreversible blockade (with buprenorphine) and Stephenson's theory of drug action. While there was good agreement between the dissociation constant (KA) of morphine in analgesia (3.3 x 10(-5) M) and in inhibition of gastrointestinal transit (1.1 x 10(-5) M), the KA of ethylketocyclazocine differed by an order of magnitude in these endpoints (3.2 x 10(-6) M and 6.7 x 10(-5) M, respectively). The efficacies of morphine were found to be similar for the two effects studied (4.23 and 5.26), while those for ethylketocyclazocine differed markedly (2.06 and 10.39). The fraction of receptors remaining unblocked after buprenorphine was consistent for the test but not for the agonist, indicating a different distribution of receptors for the two endpoints. Our results strongly suggest that morphine induces analgesia, and slows transit in the small intestine, through the same type of receptor. The same conclusion cannot be drawn for ethylketocyclazocine.

Analgesia↗
PubMed1982

EEG, EMG and behavioral evidence for the involvement of endorphin systems in postictal events after electroconvulsive shock in rats.

We studied the effects of transauricular electroshock (ECS) on EEG and EMG patterns, and overt behaviors (wet-dog shaking and excessive grooming), caused by RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2', 8',14 codeinone) in rats. Male, Sprague Dawley rats were prepared with cerebrocortical EEG and temporalis muscle EMG electrodes. In sham-shocked rats, RX 336-M (6 mg/kg, i.p.) induced behavioral activation, rapid forepaw movements, wet-dog shaking and excessive grooming; this syndrome was associated with EEG activation and EMG spiking. ECS alone produced a generalized seizure followed by postictal EEG slowing and behavioral depression. ECS suppressed the RX 336-M-induced behavioral syndrome and associated EEG and EMG responses. This attenuating action of ECS, presumed to involve the release of endogenous opioids, was antagonized when the rats were pretreated with naloxone (10 mg/kg, s.c.). Our results provide further evidence for the view that endogenous opioids are involved in the pathophysiology of certain postictal phenomena.

Animals↗
PubMed1982

Morphine-receptor dissociation constant and the stimulus-effect relation for inhibition of gastrointestinal transit in the rat.

The dissociation constant (KA) of morphine for its receptors was determined by the method of partial irreversible blockade of the receptor population using inhibition of gastrointestinal transit of a forced charcoal meal as the pharmacological endpoint. The anti-motility effect of morphine was antagonized when rats were pretreated with buprenorphine (0.3 mg/kg s.c.), a narcotic antagonist analgesic, 30 min before morphine and the extent of gastrointestinal transit was estimated a further 45 min later. With this schedule of drug administration, the agonist action of buprenorphine is minimal and its antagonist action predominates. The value of KA was (1.1 +/- 0.2) x 10(-5) mol/kg, a value close to that previously reported (2.9 x 10(-5) mol/kg) by us with these compounds in the rat tail flick test. The value of [A50], found here was 2.15 x 10(-6) mol/kg, approximately 1/5 of that of KA. Also, the stimulus-effect relation of the tissue, defined in Stephenson's theory, was plotted and found to be nonlinear. This result, when coupled with the inequality of KA and [A50], argues against the application of classical drug-receptor theory to this system. The apparent agreement between KA values for antinociception and inhibition of gastrointestinal transit is interesting, but does not necessarily prove equivalent receptors mediating the two different effects.

Animals↗
PubMed1982

A quantitative analysis of the shaking behavior induced in rats by beta-endorphin and [D-Ala2, Met5]enkephalinamide.

beta-Endorphin (5-80 microgram) or [D-Ala2,Met5]enkephalinamide (DALA) (5-40 microgram) was administered intracerebroventricularly to rats. With both opioid peptides, there was no direct relationship between log dose and mean number of wet-dog shakes (WDS) that occurred during the following 15 min. When the results were analyzed quantitatively, the dose of DALA that caused 50% of the rats to shake at least twice was 8.6 microgram (4.9-15 microgram). beta-Endorphin had such poor efficacy that an ED 50 could not be obtained. Morphine (1 and 5 mg/kg, s.c.) antagonized shaking caused by the optimal dose of DALA (20 microgram). Naloxone (0.1-10 mg/kg, s.c.) attenuated both DALA- and beta-endorphin-induced WDS in a dose-related manner. This latter result differentiates shaking associated with opioid peptides from that caused by thyrotropin releasing hormone (TRH), another endogenous stimulant of WDS in rats. There was no cross-tolerance between RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone), a novel shake inducing agent, and beta-endorphin. This finding again differentiates beta-endorphin-induced shaking from that caused by TRH and also from that associated with several exogenous stimulants of WDS.

Animals↗
PubMed1982

A study of the shaking and grooming induced by RX 336-M in rats.

Several endogenous peptides and experimental agents induce "wet-dog" shakes and excessive grooming after acute administration to rats, but quantitative information on a possible relationship between the two behaviors is lacking. RX 336-M (7,8-dihydro-5'-6'-dimethylcyclohex-5'-eno-1',8',14 codeinone) is a novel compound which elicits dose-related shaking and grooming in the rat. We have measured and compared the shaking and grooming induced by several doses of RX 336-M (1.5-12 mg/kg, IP) in male Sprague Dawley rats at various stages of maturation. Analysis of the correlation between the number of "wet-dog" shakes and the frequency of grooming episodes indicates that a relationship may exist between the shaking and grooming. The excessive grooming induced by RX 336-M may be a mechanism by which the rat's state of arousal (raised by the shaking) is lowered and homeostasis is maintained.

Age Factors↗