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Biomedical subjects

J L Vaught

Publications and source records attributed to J L Vaught.

At least 73 records · Page 4Linked to original sources
PubMed1985

Mu and delta, but not kappa, opioid agonists induce contractions of the canine small intestine in vivo.

Extraluminal strain gage transducers were sutured along the transverse axis of the duodenum in order to monitor circular muscle contractile activity in the pentobarbital anesthetized dog. Administration by intravenous bolus of a variety of mu- and delta-directed opioid ligands resulted in a dose-dependent increase in duodenal contractile activity. In contrast, all kappa-directed ligands were devoid of stimulatory activity. Naloxone reversed the effects of normorphine and [Met5]enkephalin but was 20 times more effective against normorphine than [Met5]enkephalin. Based on the inactivity of all kappa ligands examined and the differential potency of naloxone against [Met5]enkephalin and normorphine, we suggest that this model may be useful in the classification of opioid ligands as to their receptor selectivity in vivo. Further, these data indicate that the stimulation of duodenal contractile activity is not mediated by enteric kappa receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1985

A comparison of the antinociceptive responses to the GABA-receptor agonists THIP and baclofen.

The antinociceptive action of the gamma-aminobutyric acid (GABA) agonists THIP and baclofen was evaluated in mice using hot-plate (48 and 55 degrees C) and tail-immersion (50 degrees C) procedures. It was found that atropine reversed antinociception induced by THIP but not that induced by baclofen in the 48 degrees C test, whereas the anticholinergic drug blocked the response to both GABA agonists when the stimulus was provided by a 55 degrees C hot-plate. Atropine methylnitrate, mecamylamine, picrotoxin and bicuculline had no effect on antinociception induced by THIP or baclofen. Prior treatment with haloperidol enhanced only the response to baclofen on the 55 degrees C hot-plate. A reciprocal cross-tolerance was found between THIP and baclofen in the tail-immersion assay, although only THIP exhibited cross-tolerance to morphine. These results suggest that while the analgesic response to THIP and baclofen is partially mediated by a common system, the two agents act by independent mechanisms as well.

Analgesics↗
PubMed1984

[D-Arg]Kyotorphin-induced ipsilateral rotation: evidence for in vivo effects independent of Met-enkephalin release.

Kyotorphin (Tyr-Arg) and its stable analogue [D-Arg]kyotorphin were injected into the substantia nigra of rats. Intranigral [D-Arg]-kyotorphin resulted in consistent ipsilateral rotational behavior which was naloxone-reversible. In comparison, intranigral Met-enkephalin induces naloxone-sensitive contralateral rotation. These results indicate a pharmacological effect of [D-Arg]kyotorphin in the substantia nigra that would appear to be independent of Met-enkephalin release.

Animals↗
PubMed1984

Physical dependence produced by chronic intracerebroventricular infusion of [D-Arg]kyotorphin or thiorphan to rats.

Two compounds, [D-Arg]kyotorphin and thiorphan, unique in their mechanisms for producing an opioid-like analgesic response, were infused for six days into the lateral cerebral ventricle of rats. [D-Arg]kyotorphin (62.5 micrograms/microliter per h) and thiorphan (75 micrograms/5 microliter per h), but not vehicle infused animals, displayed certain behaviors characteristic of precipitated morphine withdrawal upon naloxone (10 mg/kg i.p.) challenge. Acute intracerebroventricular (i.c.v.) administration of [D-Arg]kyotorphin (62.5 micrograms/5 microliter) or thiorphan (75 micrograms/5 microliter) and subsequent challenge with naloxone resulted in no abnormal behavior. These data indicate that compounds which produce their analgesic effect through the modulation of endogenous opioids can cause physical dependence.

Amino Acids, Sulfur↗
PubMed1984

Tachykinin-like central activity of neuromedin K in mice.

Neuromedin K, a decapeptide isolated from porcine spinal cord and suggested to have tachykinin-like activity in vitro, produced reciprocal hind-limb scratching when injected intrathecally to mice. Neuromedin K was 20-60 times less potent in producing scratching (on a molar basis) than substance P, kassinin, eledoisin or physalaemin. The activity of neuromedin K was blocked by the substance P antagonist [D-Pro2D-Trp7.9]substance P at doses of antagonist which effectively blocked the activity of the other tachykinins. These data provide the first evidence for tachykinin-like activity of neuromedin K in the central nervous system.

Animals↗
PubMed1984

Differential analgesic cross-tolerance to morphine between lipophilic and hydrophilic narcotic agonists.

Mice were rendered tolerant to morphine by the subcutaneous implantation of one 75 mg morphine pellet. Seventy-two hours post-pellet implantation, the animals were evaluated in the tail-flick assay for analgesic tolerance and cross-tolerance to subcutaneously administered morphine, normorphine, methadone, etorphine and intracerebroventricularly administered morphine. With the pellet remaining in situ during testing, there was the expected analgesic tolerance to peripherally administered morphine and analgesic cross-tolerance to normorphine. However, with the pellet in situ during testing, there was a surprising lack of analgesic tolerance to intracerebroventricular administered morphine and no analgesic cross tolerance to peripherally administered etorphine or methadone. In contrast, removal of the morphine pellet 3 hours prior to the analgesic evaluation apparently unmasked the expression of tolerance and cross-tolerance as evidenced by a three fold, parallel shift to the right of the analgesic dose-response curve for subcutaneously administered etorphine and methadone and a seven fold shift to intracerebroventricularly administered morphine. These data emphasize that a more rigorous evaluation of tolerance development methodologies need be explored and support the suggestion that removal of the morphine-inducing pellet prior to analgesic determinations results in a distinct state of "tolerance" quite different from that observed with the pellet remaining in situ during testing.

Analgesics, Opioid↗
PubMed1983

Evaluation of the interactions of mu and delta selective ligands with [3H]D-Ala2-D-Leu5-enkephalin binding to mouse brain membranes.

The interactions of putative mu and delta selective ligands with [3H]D-ala2-D-leu5 enkephalin (DADLE) binding to mouse brain membranes were investigated. Computerized curve fitting of displacement curves performed at three different concentrations of 3H-DADLE indicated that a one site competitive model was sufficient to explain the interactions of leu-enkephalin (LE) and D-ser2-thr6-leucine enkephalin with 3H-DADLE binding. Similar experiments with morphine and morphiceptin were unique in that the multiple displacement curves crossed over one another. A two-site competitive model was required to adequately describe the interactions of these mu selective ligands with 3H-DADLE. This two-site model was one in which the inhibitor had higher affinity for the site labeled with lower affinity by 3H-DADLE. However, this two site model did not correctly predict the interaction of LE with 3H-DADLE in the presence of morphiceptin. These data indicate that: 1) putative mu and delta selective ligands do not bind to a common high affinity site; 2) mu selective ligands are not simple mixed inhibitors of a single site labeled by 3H-DADLE; and 3) competitive binding models may not explain the interaction of mu ligands with 3H-DADLE binding.

Animals↗
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

Comparison of the filtration and centrifugation methods for assaying [3H](D-ala2, D-leu5)enkephalin binding to mouse brain membranes.

The binding of [3H](D-ala2, D-leu5)enkephalin (DADLE) to mouse brain membranes was studied via rapid filtration with GF/C filters and via the centrifugation method. The amount of specific binding determined by filtration was found to be dependent on the length of time between the initiation of vacuum and the actual time of filtration. Vacuum strength alone also significantly affected the amount of specifically bound [3H]DADLE measured by filtration. The centrifugation method increased the number of experimentally determined binding sites when compared to the filtration method. The difference in the number of binding sites was only partially attributable to passage of binding material through the GF/C filter. The ability of morphine to displace [3H]DADLE was also found to differ slightly between the two methods. These data indicate that centrifugation is a better method of determining the binding parameters of [3H]DADLE in mouse brain membrane preparations.

Animals↗
PubMed1983

Multidimensional analysis of ligand binding data: application to opioid receptors.

The existence of distinct mu and delta opioid receptors is now well accepted. Most investigators favor the hypothesis that these receptors are physically distinct and that the enkephalins are only 2-10 fold selective for the delta receptor. Rothman and Westfall (Mol. Pharmacol. 21:548-557) recently challenged this hypothesis, proposing that at least some population of mu and delta receptors coexist in an opioid receptor complex and that the enkephalins are at least 100 fold selective for the delta receptor. In this paper we describe a generally applicable method we have used to design and analyze ligand binding experiments which distinguish between the two different models.

Animals↗
PubMed1982

The effects of receptor selective opioid peptides on morphine-induced analgesia.

Utilizing the mouse tail-flick assay, four opioid peptides, which have been reported to be selective for either mu- or delta-opioid receptors, were examined for their analgesic potency and for their ability to modify morphine-induced analgesia. [D-Ala2,D-Leu5]enkephalin and [D-Ser2,Thr6]leucine-enkephalin, putative delta-receptor selective peptides, produced a potent analgesic response and at subanalgesic doses potentiated morphine-induced analgesia. Morphiceptin and [D-Ala2,Pro5]enkephalinamide, putative mu-receptor selective peptides, were similarly found to produce analgesia. However, in contrast to the delta-receptor selective peptides, three mu-receptor selective peptides were unable to alter the potency of morphine. Thus, it would appear that the potentiation of morphine analgesia is a unique property of delta-receptor selective peptides.

Analgesia↗
PubMed1982

Mu and delta receptors: their role in analgesia in the differential effects of opioid peptides on analgesia.

Utilizing the mouse tail-flick assay, the rank order of analgesic potency for various opioids (i.c.v.) is beta h-endorphin greater than D-Ala2-D-Leu5-enkephalin greater than morphine greater than D-Ala2-met-enkephalinamide much greater than met-enkephalin much greater than leu-enkephalin. Assuming mu receptor mediation of analgesia, there is an affinity and analgesic potency (ie: D-Ala2-Leu5-enkephalin has 1/7 the affinity of morphine for the mu receptor but is 18X more potent as an analgesic). Additionally, sub-analgesic doses of various opioid peptides have opposite effects on analgesic responses. Leu-enkephalin, D-Ala2-D-Leu5-enkephalin or beta h-endorphin potentiate morphine or D-Ala2-met-enkephalinamide analgesia whereas met-enkephalin or D-Ala2-met-enkephalinamide antagonize opioid-induced analgesia. Using the enkephalins as the prototypic delta ligands (100 fold selective) and based on their effects on analgesia, we suggest that Leu-enkephalin-like peptides interact with the delta receptor as an "agonist" to facilitate and met-enkephalin-like peptides as an "antagonist" to attenuate analgesia. Given the biochemical evidence of a coupling between mu and delta receptors, we suggest that the mechanism of facilitation or attenuation of analgesia by the enkephalins is a direct in vivo consequence of this coupling. Further, the analgesic potencies of various opioid ligands can be better correlated to the combination of their simultaneous occupancy of mu and delta receptors.

Animals↗
PubMed1982

A characterization of kyotorphin (Tyr-Arg)-induced antinociception.

Intracerebroventricular administration of kyotorphin (Tyr-Arg) or Tyr-D-Arg to mice or intrathecal administration of kyotorphin to rats resulted in a dose-dependent, long-lasting, naloxone-reversible analgesia as measured by the 48 degrees C hot plate assay. The potency of kyotorphin was equal to that of Met-enkephalin although its duration of action was substantially longer. Cross-tolerance to kyotorphin could be demonstrated in animals made tolerant to morphine by chronic morphine pellet implantation. Kyotorphin was found to be inactive against column purified enkephalinase A, B and aminopeptidase and indirect evidence would suggest a lack of Met-enkephalin-releasing effect. Thus, kyotorphin represents a unique, naturally occurring peptide with in vivo narcotic-like characteristics and an unknown mechanism of action quite distinct from other opioid peptides.

Analgesics↗
PubMed1981

A characterization of dynorphin-(1-13) on the guinea pig ileal longitudinal muscle.

Using naloxone as the antagonist, a comparison of pA2 values obtained from the guinea pig ileal longitudinal muscle preparation revealed that the pA2 value for dynorphin-(1-13) was significantly different from that of the pure narcotic agonists such as morphine, beta h-endorphin, Leu- and Met-enkephalin and that of the mixed agonist-antagonists such as nalorphine. In addition, no cross-tolerance to dynorphin-(1-13) could be demonstrated whereas a pronounced cross-tolerance existed for other opioid peptides on a ileal strip made tolerant to morphine by implantation of morphine pellets to the guinea pig for 72 h. Thus, dynorphin-(1-13) would appear to have a unique pharmacology on this peripheral opioid receptor preparation quite distinct from that of other known opioid peptides.

Animals↗
PubMed1980

The potentiation of spinal analgesia by leucine enkephalin.

In two strains of rats, intrathecal administration of morphine and met-enkephalin was found to produce a dose-dependent analgesic effect as measured by the tail-flick assay. Prior administration of leu-enkelphalin at a dose which had no analgesic effect was found to reduce significantly the analgesic ED50 of both morphine and met-enkephalin. Met-enkephalin pretreatment, at a similar sub-analgesic dose, was without effect. Thus, a differential interaction of the enkephalins with morphine is evident at spinal structures.

Anesthesia, Spinal↗