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A G Hayes

Publications and source records attributed to A G Hayes.

At least 55 records · Page 3Linked to original sources
PubMed1988

In-vivo studies with the opioid antagonist, 16-methylcyprenorphine.

The effect of the opioid antagonist, 16-methylcyprenorphine (RX8008M), on the antinociceptive action of the mu-selective agonist, morphine, and the kappa-selective agonist, U50488H, has been investigated in the mouse abdominal constriction test. RX8008M produced a dose-dependent antagonism of the antinociceptive effect of morphine, but did not antagonize the response to U50488H. RX8008M should prove a useful probe for the in-vivo characterization of the receptor selectivity of opioid drugs.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1988

Evidence that the kappa agonist U50488H has non-opioid actions.

The antagonism of the antinociceptive effects of various kappa-opioid agonists has been studied in the mouse abdominal constriction test. Naloxone produced a much smaller degree of antagonism of U50488H than it did of two other kappa-agonists, U69593 and tifluadom. The kappa-selective antagonist, norbinaltorphimine, also failed to shift the dose-response curve to U50488H in this test, despite producing considerable antagonism of the U50488H effect in the rotarod test and of U69593 in both experimental situations. These results are suggestive of a non-opioid component to the action of U50488H in the abdominal constriction test. At high concentrations, U50488H, but not U69593, also showed non-opioid effects in reducing contractile activity in the field-stimulated isolated guinea-pig ileum, as demonstrated by the profile of antagonism seen with beta-chlornaltrexamine and naloxone. These results suggest that U69593, rather than U50488H, may be the kappa-agonist of choice to use, particularly in in-vivo experiments.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1987

Norbinaltorphimine: antagonist profile at kappa opioid receptors.

The pharmacological profile of the opioid antagonist norbinaltorphimine has been characterised in vitro and in vivo. In vitro, norbinaltorphimine reversibly antagonised the effects of kappa agonists with pA2 values of 10.2-10.4. Norbinaltorphimine was much less potent as an antagonist at mu and delta receptors, pA2 values were 7.4-7.6 and 7.6-7.8, respectively. In all cases Schild slopes were unity. In vivo, norbinaltorphimine was an effective antagonist only at high dose levels and was not very selective between mu and kappa. The results indicate that in vitro norbinaltorphimine is a potent selective kappa antagonist; however, this antagonist profile is not maintained in vivo.

Animals↗
PubMed1987

Differential sensitivity of models of antinociception in the rat, mouse and guinea-pig to mu- and kappa-opioid receptor agonists.

1 A range of opioid receptor agonists were tested for activity in five antinociceptive models: the acetylcholine-induced abdominal constriction, tail-flick and hot plate tests in the mouse and the paw pressure test in the rat and guinea-pig. 2 Agonists acting preferentially at the kappa-opioid receptor were significantly more potent in the guinea-pig than in the rat paw pressure test, whereas mu-receptor preferring agonists were equipotent in the two tests. The mouse abdominal constriction test was of equal sensitivity to the guinea-pig pressure test for both types of agonist. 3 The mouse tail-flick and hot plate tests were progressively less sensitive than the other three tests, particularly to kappa-receptor preferring agonists. 4 The efficacy of an agonist can also markedly affect its activity in antinociceptive tests. Thus, partial kappa-agonists were weak or inactive in the rat paw pressure test, and partial agonists at both mu- and kappa-opioid receptors were relatively weak in the tests in which heat was the noxious stimulus, particularly the mouse hot plate test. 5 The mouse abdominal constriction test is suggested as the most appropriate antinociceptive model for testing a broad range of opioid agonists, whilst the relative potency of a drug in the rat and guinea-pig paw pressure tests may indicate the degree to which it is selective for kappa-opioid receptors in vivo.

Animals↗
PubMed1987

Evaluation of the receptor selectivities of opioid drugs by investigating the block of their effect on urine output by beta-funaltrexamine.

The effects of a series of opioid drugs on urine output in the water-loaded rat were studied and also the block of those effects by the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA). Fentanyl, d-propoxyphene, profadol, bromadoline, buprenorphine and nalbuphine produced only a decrease in urine output, which was antagonised by pretreatment with beta-FNA, 40 mg/kg s.c., 24 hr beforehand. These drugs were thus characterized as selective mu receptor agonists. U-50,488, tifluadom, Mr2034, proxorphan, ethylketocyclazocine and butorphanol all produced an initial decrease in urine output, which was antagonized by beta-FNA, and therefore probably mu receptor mediated, followed by a beta-FNA insensitive diuretic effect, which was probably kappa receptor mediated. For U-50,488, tifluadom, Mr2034 and proxorphan the threshold dose for increasing urine output was lower than that for decreasing it, suggesting that these four compounds are kappa-selective agonists. For ethylketocyclazocine and butorphanol, the threshold doses for producing both effects were similar, suggesting that these two drugs are non-selective agonists. SKF 10,047 produced a diuretic effect at low dose-levels, which may be kappa receptor mediated, and a beta-FNA insensitive decrease in urine output at higher dose-levels, which may suggest a sigma receptor mediated effect.

Animals↗
PubMed1986

Pharmacology of delta-opioid receptors in the hamster vas deferens.

Electrically evoked contractions of the hamster isolated vas deferens are inhibited only by opioid drugs which have agonist activity at delta-opioid receptors. Opioids which are mu-, kappa- or sigma-selective were either inactive or were antagonists. The compound beta-funaltrexamine, which irreversibly blocks mu- and delta-opioid receptors, caused a flattening of the dose-response curve and a reduced maximum inhibition available to delta-opioid agonists. Analysis of the curves by the double-reciprocal null method enabled the affinity of these agonists at delta-opioid receptors to be calculated.

Animals↗
PubMed1986

Irreversible selective blockade of kappa-opioid receptors in the guinea-pig ileum.

The irreversible non-selective opioid antagonist beta-chlornaltrexamine (beta-CNA) was used in combination with selective mu receptor protection by [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO) to produce an effective kappa receptor antagonism in the guinea-pig field-stimulated ileum preparation. Using a standard pre-treatment of 10(-7) M beta-CNA incubated for 15 min, DAG (10(-6)-10(-4) M) protected the response to the mu agonist normorphine while reducing the antagonism of the kappa agonist U50488 to a lesser extent. The concentration of DAGO which produced the most selective protection was 10(-5) M. This method was used to find the kappa selectivity of a series of opioid agonists. Of the compounds tested, butorphanol, dynorphin-(1-17), U50488, tifluadom, bremazocine and Mr 2034 were the most kappa-selective. The correlation with kappa agonist selectivity in vitro and effects in vitro on urine output in the rat is demonstrated.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Alpha-adrenoceptor-mediated antinociception and sedation in the rat and dog.

The present study compared the potency of a range of alpha-adrenoceptor agonists in producing antinociception and sedation in the rat and dog. In the rat, the selective alpha 2-adrenoceptor agonists, guanabenz, UK 14304 and guanfacine, were more potent as sedative agents than as antinociceptive agents. For compounds which have similar activities at both alpha 1 and alpha 2-adrenoceptors, such as clonidine, alinidine, oxymetazoline and naphazoline, there was little separation between effective doses for antinociception and sedation. In marked contrast, the selective alpha 1-adrenoceptor agonists, ST 587 and methoxamine, were more potent as antinociceptive agents than as sedatives. Similarly, ICI 106,270 and CP 18,534, two agonists with a greater alpha 1 to alpha 2-adrenoceptor ratio than clonidine, were also more potent in antinociceptive tests than in sedative tests. In the conscious dog, clonidine was 8-10 times more potent than ICI 106,270 and CP 18,534 at increasing nociceptive thresholds to mild electrical stimulation of the toothpulp. At equi-antinociceptive doses, the ranked order of potency for inducing sedation was clonidine greater than or equal to ICI 106,270 greater than CP 18,534. Dose-related bradycardia was also induced by each of the three alpha-adrenoceptor agonists at antinociceptive doses. These data suggest that antinociceptive activity can probably be mediated by either alpha 1 or alpha 2-adrenoceptors, whereas sedation appears to be mediated solely by the alpha 2-subtype. Thus, it may be possible to separate the antinociceptive and sedative effects of sympathomimetic agents, but it is unlikely that these agents would be completely devoid of cardiovascular effects.

Adrenergic alpha-Agonists↗
PubMed1986

Antagonism of alpha-adrenoceptor agonist-induced antinociception in the rat.

The present study investigated the effects of WB4101, a selective alpha 1-adrenoceptor blocking agent, and idazoxan, a selective alpha 2-adrenoceptor blocking agent, on antinociception and sedation in the rat mediated by adrenoceptors. Selective alpha 1-adrenoceptor agonists, e.g. ST587 and methoxamine induced antinociception but only elicited slight sedation; their antinociceptive effects were antagonized by WB4101 but not by idazoxan. In contrast, the marked sedative and antinociceptive effects induced by the selective alpha 2-adrenoceptor agonist, UK 14,304, were attenuated by idazoxan, but were little affected by WB4101. The mixed alpha 1/alpha 2-adrenoceptor agonists, clonidine and ICI 106,270, had differing profiles with respect to their antagonist interactions; the antinociceptive and sedative effects induced by clonidine were antagonized by idazoxan, whereas the antinociceptive effects of ICI 106,270 were antagonized by WB4101. The slight sedative effects induced by ICI 106,270 were not attenuated by either WB4101 or idazoxan; therefore, these studies give no insight into the mechanism of action for sedation induced by ICI 106,270. These data suggest that antinociception may be mediated by either alpha 1 or alpha 2-adrenoceptors; whereas sedation is predominantly alpha 2-adrenoceptor mediated.

Adrenergic alpha-Agonists↗
PubMed1986

Reversal by beta-funaltrexamine of the antinociceptive effect of opioid agonists in the rat.

The effect of the irreversible opioid receptor antagonist, beta-funaltrexamine (beta-FNA), on antinociception produced by mu- and kappa-receptor agonists was studied in the rat. beta-FNA, 20 to 80 mg kg-1, s.c., given 24 h before testing, produced a dose-related antagonism of the effects of morphine in the paw pressure, hotplate and tail-flick tests. Following the 80 mg kg-1 dose, the degree of antagonism of morphine was stable for up to 48 h after dosing, but was reduced by 5 days and had disappeared by 8 days. In the paw pressure test, beta-FNA, 40 mg kg-1, s.c., antagonized the effects of fentanyl, buprenorphine, tifluadom, ethylketocyclazocine and proxorphan; it was without effect against the highly selective kappa-agonist, U-50,488. In light of these results, the possible opioid receptor selectivities of both the agonists and beta-FNA are reassessed.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1986

Cross-protection of mu and delta opioid receptors in the mouse vas deferens.

Opioid receptors in the C57/BL mouse vas deferens can be irreversibly blocked by pre-treatment with beta-chlornaltrexamine. Pre-incubation with the highly selective delta-receptor antagonist ICI 174864 concentration-dependently protected delta-receptors from inactivation, but the same concentrations similarly protected mu receptors. Pre-incubation with selective mu-receptor agonist, [D-Ala2, MePhe4, Gly(ol)5]enkephalin, also protected both mu and delta receptors to the same degree. Neither ligand protected k-opioid receptors. The results suggest that there may be a structural interaction between mu and delta receptors in the mouse vas deferens.

Animals↗
PubMed1985

Effect of mu and kappa opioid receptor agonists on rat plasma corticosterone levels.

The effect of several mu and kappa opioid receptor agonists on rat plasma corticosterone levels, measured using radioimmunoassay, was investigated. The mu agonists, morphine and fentanyl, and the kappa agonists, U-50,488, tifluadom and bremazocine, all produced dose-related increases in rat plasma corticosterone levels. The effects of both fentanyl and U-50,488 were reversed by naloxone, indicating an action at opioid receptors. Pretreatment of the rats with the irreversible, mu-selective antagonist, beta-funaltrexamine, reduced the effect of fentanyl, but not that of U-50,488, indicating that both mu and kappa opioid receptors are involved in mediating this effect.

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

Effects of opiates on urine output in the water-loaded rat and reversal by beta-funaltrexamine.

The effects of several mu and kappa opioid receptor agonists on urinary excretion were examined in the water-loaded rat. Mu agonists induced anti-diuresis whereas kappa agonists caused diuresis. Furthermore, high efficacy kappa agonists eg. U50, 488H and tifluadom, produced marked diuretic effects, whereas kappa partial agonists eg. nalorphine, produced low maximum diuresis. Compounds having activity at both mu and kappa receptors eg. ethylketocyclazocine(EKC) and MR2034, produced a biphasic effect, an initial anti-diuretic effect followed by a more sustained diuretic effect. The irreversible mu receptor antagonist, beta-funaltrexamine (beta-FNA) antagonized the anti-diuretic effects elicited by fentanyl, pentazocine and buprenorphine and the initial anti-diuretic effect induced by EKC but did not inhibit the diuretic effects induced by U50, 488H and EKC. Thus, the use of beta-FNA in the water-loaded rat provides us with a valuable in vivo test which differentiates both mixed and selective opioid receptor agonists.

Animals↗
PubMed1985

Determination of the receptor selectivity of opioid agonists in the guinea-pig ileum and mouse vas deferens by use of beta-funaltrexamine.

The irreversible inhibitor of mu-opioid receptor-mediated effects, beta-funaltrexamine (beta-FNA), was used to investigate the selectivity of various opioid agonists at mu-opioid receptors in the electrically stimulated guinea-pig ileum and mouse vas deferens preparations in vitro. In the guinea-pig ileum, pretreatment with beta-FNA (3 X 10(-8) - 3 X 10(-6)M) produced a concentration-dependent antagonism of the inhibitory effect produced by the mu-opioid receptor agonist [D-Ala2, MePhe4, Gly(ol)5]enkephalin (DAGO). High concentrations of beta-FNA (3 X 10(-6) - 1 X 10(-5)M) also antagonized the inhibitory effects of the kappa-opioid agonist U50488. Pretreatment of guinea-pig ileum with beta-FNA at 1 X 10(-6)M resulted in blockade of the effect of some opioid agonists. The compounds which showed the largest rightward shifts in their concentration-response curves, and hence the greatest mu/kappa opioid receptor selectivity, were nalbuphine, [D-Ser2, Leu5]enkephalinyl-Thr6(DSLET), morphine, DAGO and normorphine. Responses to tifluadom, Mr 2034, ethylketocyclazocine, butorphanol, nalorphine, proxorphan and U50488 were not inhibited by beta-FNA. In the mouse vas deferens, pre-treatment with beta-FNA (1 X 10(-6)M) produced a similar shift in the dose-response curves for normorphine as in the guinea-pig ileum. The concentration-response curves for the delta-receptor agonists [D-Ala2, D-Leu5] enkephalin (DADLE) and DSLET were, however, also shifted, indicating that beta-FNA will also block delta-opioid receptors. Since beta-FNA does not block kappa-opioid receptor-mediated effects, it can be used in the guinea-pig ileum preparation as a selective mu-receptor inhibitor. However, its lack of selectivity between mu- and delta-opioid receptors should be taken into account in many other isolated tissues and experiments in vivo.

Animals↗
PubMed1985

Effect of beta-funaltrexamine on opioid side-effects produced by morphine and U-50, 488H.

Pretreatment of rats with the irreversible mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA), 20-40 mg kg-1 s.c., produced a dose-related antagonism of the reduction in respiratory rate, gastrointestinal (GI) propulsion, rotarod reaction latencies and body temperature produced by morphine administration 24 h later, suggesting that these effects are mediated via mu-opioid receptors. The kappa-receptor agonist, U-50,488H, was without effect on respiratory rate at the doses tested, but produced hypothermia, sedation and low maximum inhibition of GI propulsion. These effects of U-50,488H were not blocked by beta-FNA suggesting that they are mediated via kappa-receptors.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1984

The depolarising action of capsaicin on rat isolated sciatic nerve.

The effect of capsaicin on the isolated sciatic nerve of rat was studied by extracellular recording of membrane polarisation. Capsaicin depolarised the sciatic nerve, but desensitization occurred rapidly upon repeated administration. Several other neuroactive substances, including substance P, were inactive. The depolarisation was reduced in nerves depleted of unmyelinated fibres by neonatal capsaicin treatment, suggesting that it occurs mainly in C-fibres. This depolarising action of capsaicin could explain the irritant and acute antinociceptive properties of capsaicin.

Afferent Pathways↗
PubMed1984

The effects of a series of capsaicin analogues on nociception and body temperature in the rat.

A series of capsaicin analogues have been synthesized in an attempt to try to separate the antinociceptive properties of capsaicin from its hypothermic effects. In capsaicin analogues with an unbranched alkyl side-chain of varying length, maximum antinociceptive and hypothermic activity was achieved with a chain length of 8-9 C atoms. Decreasing the chain length decreased both parameters equally. Substitution in the aromatic ring abolished activity. Several compounds related to homovanilloyl dodecylamide, an analogue of capsaicin in which the acylamide linkage is reversed, produced some antinociceptive activity without concomitant hypothermia, but the maximum antinociceptive effect achieved was very small. In the present series of capsaicin analogues good antinociception without hypothermia was not found.

Animals↗