Biomedical subjects

I Kitchen

Publications and source records attributed to I Kitchen.

At least 55 records · Page 3Linked to original sources

PubMed1993

Assessment of 8-OH-DPAT induced spontaneous tailflicks as an in vivo model of 5-HT1A function in young rats.

Spontaneous tailflicks, measured as elevation of the tail above the body axis in restrained animals, have been studied in both adult and young rats. The selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), induced dose-related increases in spontaneous tailflicks in adult (> 60 days) male rats. These responses were antagonised by the 5-HT1A antagonists (-)-propranolol and (-)-pindolol. 8-OH-DPAT (1 mg/kg) induced tailflicks could be observed in 30, 25 and 20 day old male rats and were also antagonised by (-)-propranolol and (-)-pindolol although drug-induced rotation of the 20 and 25 day old animals hindered assessment. At 14 and 10 days, 8-OH-DPAT (1 mg/kg) produced Straub tail responses which precluded the observation of tailflicks. Lower doses of 8-OH-DPAT, which did not elicit Straub tail in these younger animals also failed to produce tailflicks. Thus 8-OH-DPAT induced spontaneous tailflicks reflect in vivo activation of 5-HT1A receptors in adult and 30 day old male rats but are inappropriate for the study of 5-HT1A mediated behaviour in younger animals.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1993

Effects of beta-funaltrexamine treatment and sexual isolation in the perinatal period on the development of mu-opioid receptors and nociception.

Male and female rats were segregated from birth (sexually isolated animals). Additional litters containing both male and female pups were kept as controls (mixed-housed animals). beta-FNA (5 mg/kg) or water was administered SC at day 0 or day 7 to isolated and mixed-housed animals. The development of mu-opioid receptors and nociceptive responses in the two groups was assessed at day 7 or 14, respectively. Mu-receptor binding was measured in whole brain using (3H) DAGO as a binding ligand and nociception assessed using the tail immersion test. beta-FNA treatment depressed mu-receptors when measured 1 but no 7 days later. However, male and female rats treated at day 0 with beta-FNA had lower brain protein content. Sexual isolation had little effect on mu-receptor number and did not augment the beta-FNA effect. However, isolation increased pain sensitivity in 7-day-old animals and in 14-day-old females. beta-FNA treatment had little effect on nociceptive threshold but reversed the effects of sexual isolation.

Animals↗

PubMed1993

A method for the study of swimming stress and stress-induced antinociception in preweanling rats.

Stress-induced antinociception (SIA) which is well characterized in the adult rat can also be observed in young rats, and, by varying swimming times, it can be dissociated into opioid and nonopioid forms. However, swimming ability in the rat does not fully develop until the third postnatal week and this has precluded the study of swim SIA in neonates. We report here the development of a harness device to aid swimming in young rats which we have successfully employed down to the age of 2 days without distress to the animals. Further we have also shown the development of the opioid form of swim SIA in the rat using this device. Swim SIA is absent at days 2 and 5, but at postnatal day 10 a small level of SIA is evident which is reversed by naloxone (10 mg/kg). Swim SIA develops rapidly thereafter, and the adult profile is observed by day 25.

Aging↗

PubMed1993

Characterization and ontogeny of P1-purinoceptors on rat vas deferens.

1. The P1-purinoceptors which mediate the inhibition by adenosine of nerve-mediated contraction of the rat vas deferens have been investigated by use of the agonists N6-cyclopentyladenosine (CPA) and 5'-N-ethylcarboxamidoadenosine (NECA) and the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The ontogeny of the responses to adenosine and to the two co-transmitters which induce the contractions in this tissue, adenosine 5'-triphosphate (ATP) and noradrenaline (NA), have also been studied. 2. The order of potency for the adenosine agonists in inhibiting the nerve-mediated contractions was CPA = NECA > adenosine. Micromolar concentrations of DPCPX were required to antagonize the inhibition by adenosine and NECA of nerve-mediated responses, whereas the inhibitory effect of CPA was antagonized by nanomolar concentrations of the antagonist. 3. NECA and adenosine inhibited contractions induced by ATP (10 microM) or by NA (10 microM), NECA being at least ten fold more potent than adenosine, whereas CPA was inactive. Micromolar concentrations of DPCPX were required to antagonize the effect of adenosine on the contractions induced by ATP (10 microM). 4. Nerve-stimulated contractions could be observed in neonatal tissues from day 15 and increased with age, and could be inhibited by adenosine from this time, the potency of adenosine decreasing with age. Responses to ATP also appeared at day 15 and increased with age up to day 25, while responses to NA were present from day 10 (the earliest day tested) and decreased with age. 5. These results show that the rat vas deferens contains both prejunctional Al-receptors and postjunctional A2-receptors, and that adenosine acts on the latter populations to inhibit nerve-mediated contractions.The high potency of adenosine in the neonate and the parallel development of responses to ATP and to nerve-mediated contractions support suggestions that purinergic responses may be particularly important in neonatal tissues.

Adenosine↗

PubMed1993

Effect of delayed weaning on opioid receptor control of swim stress-induced antinociception in the developing rat.

1. The opioid type of swim-stress induced antinociception (SIA) is mediated via mu-sites in preweanling rats and predominantly by delta-sites in postweanling animals. We have studied the effect of delay of weaning on the receptor transition of this behaviour in the developing rat. 2. Litters were weaned normally at day 21 or allowed to remain with their mothers until assessment of swim SIA. Animals were stressed by warm water (20 degrees C) swimming for 3 min periods and antinociception assessed by the tail immersion test (50 degrees C). 3. Naloxone (10 mg kg-1) partially reversed swim SIA in both 25 day old weaned and non-weaned rats. 4. Naltrindole (1 mg kg-1) partially reversed swim SIA in 25 day old weaned rats but had no effect in non-weaned animals. Naltrindole (5 mg kg-1) completely abolished swim SIA in weaned rats but was without effect in non-weaned groups. Antinociceptive responses to the mu-agonist, alfentanil (60 micrograms kg-1) were unaffected by naltrindole at 1 mg kg-1 but were partially reversed at 5 mg kg-1. 5. In 30 day old non-weaned rats, naltrindole (5 mg kg-1) abolished the swim SIA. 6. In conclusion, transition from mu to delta-receptor control of swim SIA in rat pups can be delayed by between 5 and 10 days by delay of weaning. The environmental stimulus of weaning can activate opioid receptor subtype operation of biological responses in the developing animal.

Alfentanil↗

PubMed1992

Mechanisms involved in the cardiovascular responses to opioid products of proenkephalin in the anaesthetised rat.

1. Cardiovascular effects of opioid peptide products of proenkephalin, [Met] enkephalin (ME), [Leu] enkephalin (LE), [Met] enkephalyl Arg6-Phe7 (MEAP) and [Met] enkephalyl Arg6-Gly7-Leu8 (MEAGL) have been studied in urethane-anaesthetised rats. 2. ME, LE, MEAP and MEAGL produced vasodepression and bradycardia mediated by mu-opioid receptors. 3. Atypical responses to MEAP were observed in a quarter of the animals studied showing tachycardia and pressor effects. This response was probably due to the release of the dipeptide Arg-Phe which exerted its effects at sympathetic ganglia. 4. Studies with the peptidase inhibitors captopril and bestatin showed a differential potentiation of the cardiovascular effects of the proenkephalin products by inhibition of angiotensin converting enzyme and aminopeptidase. 5. The effects of vagotomy, pithing and studies with atropine, and N-methyl levallorphan were used to demonstrate that, for all four proenkephalin peptides, cardiovascular effects were mediated by peripheral opioid receptors and transmission to the CNS via vagal afferents.

Anesthesia↗

PubMed1992

Characterization of P1-purinoceptors on rat duodenum and urinary bladder.

1. The P1-purinoceptors mediating relaxation of the rat duodenum and inhibition of contraction of the rat urinary bladder were characterized by use of adenosine and its analogues 5'-N-ethylcarboxamidoadenosine (NECA), N6-cyclopentyladenosine (CPA) and 2-p-((carboxyethyl)phenethylamino)-5'- carboxamidoadenosine (CGS 21680), as well as the A1-selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The stable analogue of adenosine 5'-triphosphate (ATP), adenylyl 5'-(beta,gamma-methylene)diphosphonate (AMPPCP), was also used as previous work had indicated that it has a direct action on some P1 receptors in addition to its P2-purinoceptor activity. 2. In the rat duodenum, the order of potency of the adenosine agonists was NECA greater than or equal to CPA greater than AMPPCP = adenosine greater than CGS 21680, and DPCPX antagonized CPA and AMPPCP at a concentration of 1 nM whereas equivalent antagonism of NECA and adenosine required a concentration of 1 microM. This suggests the presence of a mixture of A1 and A2 receptors in this tissue, with CPA and AMPPCP acting on the A1 and NECA and adenosine acting on the A2 receptors. 3. In the rat bladder, the order of potency of the adenosine agonists for inhibition of carbachol-induced contractions was NECA much greater than adenosine greater than CPA = CGS 21680, and a concentration of DPCPX of 1 microM was required to antagonize responses to NECA and adenosine. This suggests the presence of A2 receptors in this tissue. ATP and AMPPCP each caused contractions which were not enhanced by DPCPX (1 microM) which suggests that in this tissue AMPPCP was acting only via P2 receptors and had no P1 agonist activity. That AMPPCP was active on the A1 receptors in the duodenum but inactive on the A2 receptors in the bladder implies that it has selectivity for the A1 subtype.4. That CGS 21680, which has been reported to bind selectively to the high affinity A2a subclass of A2 receptors, had a very low potency on the A2 receptors in the duodenum and in the bladder suggests that these receptors are of the low affinity A2b subclass.

Adenosine↗

PubMed1992

Effects of the delta-opioid receptor antagonist naltrindole on antinociceptive responses to selective delta-agonists in post-weanling rats.

1. Antagonism, by the selective delta-opioid receptor antagonist naltrindole, of the antinociceptive effects of [D-Pen2, D-Pen5] enkephalin (DPDPE), [D-Ser2, Leu5, Thr6] enkephalin (DSLET) and D-Ala2 deltorphin I (DELT I) has been studied in 25 day old rats. 2. Antinociception was measured by the 50 degrees C tail immersion test following i.p. administration of agonists and/or antagonists. 3. Dose-related antinociception was observed with DPDPE, DSLET and DELT I and ED75 doses were computed (0.66 mg kg-1, 0.65 mg kg-1, 0.032 mg kg-1 respectively) and used for antagonism studies. 4. Naltrindole (0.01 mg kg-1) significantly attenuated the antinociceptive effects of DPDPE and DSLET with 0.1 mg kg-1 producing complete reversal of the effects of the ED75 dose. In contrast, naltrindole at 0.01 and 0.1 mg kg-1 did not alter antinociceptive responses to DELT I. Naltrindole at 1 mg kg-1 significantly attenuated DELT I antinociception. 5. Naloxone (1 mg kg-1) produced equivalent degrees of antagonism of the antinociceptive effects of DPDPE, DSLET and DELT I. ICI 174,864 (1 mg kg-1) also antagonized antinociception with a differential degree of attenuation (DSLET > DPDPE > DELT I). 6. Naltrindole (1 mg kg-1) had no effect on the antinociception induced by the selective mu-agonist alfentanil (60 micrograms kg-1). Naltrindole, naloxone or ICI 174,864 had no effect on nociceptive latencies. 7. The differential antagonism by naltrindole of the effects of three selective delta-agonists suggests delta-receptor heterogeneity.Further, the lower sensitivity of response to DELT I suggests that this agent may exert its antinociceptive effects at a different 6 receptor subtype from DPDPE or DSLET.

Analgesics↗

PubMed1991

The importance of tachyphylaxis and release of cyclooxygenase products in the modulation of endothelin-1-induced responses in rat and guinea pig tracheal chains.

Responses to endothelin-1 (ET-1) were studied in both rat and guinea pig tracheal chains in vitro. Indomethacin potentiated contractile responses to ET-1 in the guinea pig but had no effect in the rat. Furthermore, relaxation responses to ET-1 observed in some guinea pig preparations only were abolished by indomethacin. Studies using repeated full cumulative dose-response curves and repeated single-dosing techniques demonstrated tachyphylaxis to ET-1 in both rat and guinea pig. However, the degree of tachyphylaxis in the guinea pig was dependent on the initial response to the peptide, and in single-dose studies in this species, tachyphylaxis to ET-1 was more prominent in the presence of indomethacin. It is suggested that both tachyphylaxis and inconsistent release of cyclooxygenase products may be responsible for the wide differences in potency estimates for ET-1 that have been observed in airways smooth muscle.

Animals↗

PubMed1991

Direct effects of adenylyl 5'-(beta,gamma-methylene)diphosphonate, a stable ATP analogue, on relaxant P1-purinoceptors in smooth muscle.

1. Previous results obtained with the rat colon muscularis mucosae, which contracts in response to adenosine and adenosine 5'-triphosphate (ATP), had suggested that adenylyl 5'-(beta,gamma-methylene)diphosphonate (AMPPCP), a stable ATP analogue, acted on P1-purinoceptors rather than, as expected, on P2-purinoceptors. This possibility has been examined in two tissues in which adenosine and ATP both cause relaxation, the guinea-pig taenia caeci and the rat duodenum. 2. ATP, 2-methylthio-ATP (2-MeSATP), AMPPCP, adenosine 5'-(alpha,beta-methylene)triphosphonate (AMPCPP) and adenosine each relaxed the taenia caeci and the duodenum, and the order of potency of the nucleotides in each tissue was 2-MeSATP greater than ATP greater than AMPCPP greater than AMPPCP, indicating that these effects were mediated by P2Y-purinoceptors. 3. The P1 antagonist 8-(p-sulphophenyl)theophylline (8-SPT) (100 microM) did not affect the responses to ATP, 2-MeSATP or AMPCPP in either tissue, but inhibited the responses of adenosine and of AMPPCP in both tissues. In the duodenum a lower concentration of 8-SPT caused a parallel shift to the right of the concentration-response curve to adenosine and to AMPPCP but to different extents, with AMPPCP being inhibited more powerfully than adenosine. A dose-ratio of around 5 was observed for adenosine and AMPPCP at concentrations of 8-SPT of 20 microM and 2 microM respectively, but Schild analysis resulted in plots with slopes greater than unity. In the taenia caeci, however, 8-SPT inhibited adenosine more powerfully than AMPPCP, and a range of concentrations (10-20 microM) only caused a two fold shift in the concentration-response curve for AMPPCP, although the concentration-response curve to adenosine was shifted in a concentration-dependent manner and Schild analysis gave a pA2 value of 5.13 with a slope of 0.90.4. As has been shown in other tissues, including the guinea-pig taenia caeci, ATP (100 microM) was rapidly dephosphorylated by enzymes present in the rat duodenum, with less than 10% remaining after 20min incubation, whereas AMPPCP (100 microM) was resistant to degradation, with greater than 90% remaining at the same time point.5. AMPPCP therefore has pronounced but variable agonist actions on P,-purinoceptors, and appears to act entirely via these receptors on the rat duodenum although in the guinea-pig taenia caeci this action is less important and it acts largely via P2y-purinoceptors. These Pl-purinoceptor effects of AMPPCP are direct and are not due to its degradation to adenosine.

Adenosine↗

PubMed1990

Ontogenesis of kappa-opioid receptors in rat brain using [3H]U-69593 as a binding ligand.

The ontogenesis of kappa-opioid receptors has been studied in the postnatal period from day 5 to day 30 using the highly selective kappa-site ligand [3H]U-69593 in binding studies. Analyses of saturation curves revealed a marked increase in the binding capacities between day 5 and day 10 with no further increment in the number of sites up to adult ages confirming a distinct ontogenetic profile from mu- and delta-sites. When expressed per mg protein the number of sites declined from day 10 to adult. At all postnatal ages there was little change in receptor affinity. This ontogenetic profile is broadly in agreement with studies using non-selective kappa-ligands but the number of sites labelled by [3H]U-69593 is markedly lower in both the neonate and the adult.

Animals↗

PubMed1990

Non-opioid effects of N-methyl levallorphan in the anaesthetised rat.

1. The effects of the quaternary opioid antagonist N-methyl levallorphan upon cardiovascular responses to non-opioid agonists has been studied in the urethane-anaesthetised rat. 2. N-methyl levallorphan showed an initial nicotinic agonist effect followed by pronounced ganglion blocking activity after intravenous administration. These effects are observed at doses only 2-fold higher than those required to block cardiovascular responses to [Met] enkephalin. 3. The narrow selectivity of N-methyl levallorphan makes this compound inappropriate for opioid antagonist studies where nicotinic receptors may be involved.

Acetylcholine↗

PubMed1990

Multiple opioid receptors mediate the respiratory depressant effects of fentanyl-like drugs in the rat.

1. Respiratory depressant effects of five drugs of the fentanyl series have been studied in anaesthetised rats. 2. The potency ratios of the fentanyl drugs to produce apnea and depress minute volume were dissimilar. Further, in vivo naloxone pA2 values were identical for blockade of apnea for the fentanyl drugs but different for antagonism of minute volume. 3. Differences in agonist potency and in naloxone pA2 values were also seen in vagotomised rats where only depression of minute volume is observed. 4. The data suggests that multiple receptor interactions are involved in the respiratory depressant effects of these drugs; the apnea response is primarily mediated through peripheral mu receptors but minute volume depression involves both mu receptors and non-mu sites.

Alfentanil↗

PubMed1990

Effect of perinatal lead exposure on morphine tolerance in the neonatal rat.

Administration of lead (at 300 and 1000 ppm) in the maternal drinking water from conception to postnatal day 10 increased the sensitivity of 10-day rat pups to noxious stimuli and disrupted the dose-response relationship to morphine antinociception. Lead-exposed rats could be made tolerant to morphine over a 5-day period (twice daily injections of 5 mg/kg morphine, postnatal days 5-10) and antinociceptive responses in tolerant rats were also disrupted by lead exposure.

Animals↗

PubMed1990

Lack of effect of perinatal lead exposure on kappa-opioid receptor function.

The effects of lead exposure have been studied upon the behavioural and diuretic responses to the kappa-opioid receptor agonist U-50488H in neonatal rats. Lead was administered in the maternal drinking water (100, 300 and 1000 ppm) from conception to postnatal day 14. The hyperactivity, wall climbing behaviours and diuretic effects of U-50488H (0.1-30 mg/kg, i.p.) in 5- and 20-day-old rat pups were unaffected at all 3 lead dose levels. Lead treatment per se produced a decrease in activity at 20 days. These results contrast with our previously reported disruption of mu- and delta-opioid receptor systems following perinatal lead exposure and suggest that the toxic effects of this metal may be confined to particular types of opioid receptor.

Animals↗

PubMed1990

Antagonism of swim-stress-induced antinociception by the delta-opioid receptor antagonist naltrindole in adult and young rats.

1. The availability of the non-peptide delta-opioid receptor antagonist naltrindole has provided the possibility for in vivo studies on the function of delta-opioid receptors. We have studied the effects of naltrindole on swim-stress-induced antinociception in adult and neonatal rats. 2. Adult, 25 and 20 day old rats were stressed by warm water (20 degrees C) swimming for 3 min periods and antinociception was assessed by the tail immersion test (50 degrees C). 3. Naltrindole (0.5 and 1 mg kg-1) antagonized swim-stress-induced antinociception in adult and 25 day old rats but in 20 day old rats naltrindole (1 mg kg-1) was without effect. 4. Antinociception induced by the highly mu-opioid receptor selective agonist alfentanil was completely antagonized by naloxone (1 mg kg-1) but virtually unaffected by naltrindole (1 mg kg-1). 5. Neither naloxone nor naltrindole (1 mg kg-1) antagonized swim-stress-induced rises in plasma corticosterone in adult rats at the time of peak antinociception. 6. In conclusion, naltrindole shows in vivo antagonism of opioid-mediated responses. Swim-stress-induced antinociception is mediated through the delta-opioid receptor in 25 day old and adult rats and through the mu-opioid site in 20 day old animals.

Aging↗

PubMed1990

The ontogeny of purinoceptors in rat urinary bladder and duodenum.

1. The ontogeny of responses to purines and analogues of smooth muscle preparations was studied in rat duodenum and rat urinary bladder. 2. Responses to adenosine and to adenosine 5'-triphosphate (ATP) mediated by P1- and P2-purinoceptors respectively were present as early as postnatal day 2, the earliest day studied. 3. In rat bladder, adenosine was inhibitory and ATP and adenosine 5'-(beta, gamma-methylene) triphosphonate (AMP-PCP) were excitatory, acting on the P2X subtype of P2-purinoceptors. Adenosine was more potent in the neonate than in the adult, while the potency of the nucleotides initially increased with age but then declined, being highest between postnatal days 10 and 25. 4. In rat duodenum also, adenosine was inhibitory, its potency being less than the adult before day 15. 5. ATP at low concentrations was inhibitory in rat duodenum at every age studied and its potency increased with age, but higher concentrations of ATP (3 microM and above) were excitatory until day 15. Both relaxations and contractions were mediated by the P2Y subtype of P2-purinoceptors. These ATP-induced contractions were not inhibited by indomethacin (25 microM) or by tetrodotoxin (1 microM) and are therefore not due to prostaglandin synthesis or to ATP-induced release of transmitter substances from nerves. 6. These results show that responses to adenosine and to adenine nucleotides are present from birth and vary with age, and that the changes seen indicate a differential development for P1-, P2X- and P2Y-purinoceptors.

Aging↗

PubMed1989

Behavioural effects of selective mu-, kappa-, and delta-opioid agonists in neonatal rats.

The behavioural effects of selective mu-, kappa- and delta-opioid agonists in 5-, 10- and 20-day-old rats were investigated by observational analysis. The predominant response to mu-agonists was behavioural depression. High doses (10 mg/kg IP) of morphine and DAGO (D-Ala2, NMe-Phe4, Glyol5-enkephalin) produced overt sedation in all the age groups and also induced catalepsy which was particularly apparent in the 5- and 10-day-old animals. These compounds did not produce any signs of behavioural activation in the neonatal rats. In contrast, rat pups treated with the kappa-agonists U50,488H and PD 117,302 (1,10 mg/kg IP) exhibited marked hyperactivity with increases in wall-climbing and locomotion. Sedative effects of the highest dose of the kappa-agonists began to emerge, however, as the animals grew older, resulting in significant decreases in behaviours such as gnawing and grooming at 20 days of age. The kappa-agonist (+)-tifluadom (0.1-10 mg/kg), but not its corresponding (-)-isomer, produced an increase in activity in 5-day-old rats, thus extending the observations made with U50,488H and PD 117,302 and establishing the stereoselective nature of the response. The involvement of kappa-receptors in opioid-induced hyperactivity was further substantiated by using a variety of opioid antagonists. In this context, the increase in activity induced by U50,488H (10 mg/kg) in 5-day-old neonates was attenuated by naltrexone (1 mg/kg IP) but not by larger doses (10 mg/kg) of either M8008 (which has low affinity for kappa-receptors) or the selective delta-receptor antagonist ICI 174,864.(ABSTRACT TRUNCATED AT 250 WORDS)

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