Genital grooming and emesis induced by vanilloids in Suncus murinus, the house musk shrew.

The potential of resiniferatoxin and capsaicin to modulate emesis and genital grooming was investigated in Suncus murinus. Resinifertoxin (3-30 nmol, i.c.v.), E-capsaicin (10-100 nmol, i.c.v.) and Z-capsaicin (100 nmol, i.c.v.) induced emesis (P<0.05) and subsequently antagonised the emetic response induced by intragastric copper sulphate (480.6 micromol/kg; P<0.05). However, resiniferatoxin failed to affect nicotine-induced (30.7 mol/kg, s.c.) emesis (P>0.05). Only resiniferatoxin induced genital grooming that was antagonised (P<0.05) by capsazepine (300-600 nmol, i.c.v.) and ruthenium red (3 nmol, i.c.v.). E-capsaicin-induced emesis was antagonised by capsazepine (300-600 nmol, i.c.v.; P<0.05) and ruthenium red (3 nmol, i.c.v.; P<0.05) but resiniferatoxin-induced emesis was resistant to capsazepine (30-600 nmol, i.c.v.; P>0.05). The emetic action of resiniferatoxin but not E-capsaicin was subject to tachyphylaxis. In cross-tachyphylaxis experiments, E-capsaicin reduced the genital grooming induced by resiniferatoxin (P<0.05). The data are discussed in relation to the classification of vanilloid receptors and mechanisms involved in emesis and genital grooming.

Cisplatin-induced emesis in the cat: effect of granisetron and dexamethasone.

The emetic action of cisplatin was investigated in the cat using a closed circuit video recording system. In initial investigations, cisplatin 3 and 5 mg/kg, i.v. induced emesis over a 2-day period following a latency of 17.6+/-9.6 and 15.6+/-7.8 h, respectively. The anti-emetic efficacy of granisetron and dexamethasone was investigated in the cisplatin 5 mg/kg, i.v.-induced emesis model. In these experiments, cisplatin induced 47.0+/-14.0 and 20.0+/-9.0 retches+vomits on days 1 and 2, respectively, following a latency of 2.4+/-0.4 h. Granisetron (1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response induced by cisplatin on days 1 and 2 by 100.0% (P<0.05) and 75.0% (P<0.05), respectively; dexamethasone (0.01-1 mg/kg, i.m.) administered three times per day reduced significantly the retching+vomiting response by 68.8-100.0% (P<0.05) and 33.3-100.0% (P<0.05) on days 1 and 2, respectively. The emetic action of cisplatin 7.5 mg/kg, i.v. was also investigated. This dose of cisplatin-induced emesis following a latency of 1.2+/-0.2 h and comprised 119.0+/-20.8 retches+vomits over a 24-h period. Granisetron and dexamethasone antagonized the emesis occurring in the first 3-h period (P<0.05) but were less effective to antagonize the subsequent emetic response (P0.05). The pharmacological sensitivity of low dose cisplatin-induced emesis in the cat is variable but unique and not representative of the clinical situation.

Modulation of emesis by fentanyl and opioid receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic mechanism of action of fentanyl to inhibit nicotine (5 mg/kg, s.c.)-induced emesis was investigated in Suncus murinus. The anti-emetic action of fentanyl (40 microg/kg, s.c.) was antagonised by the opioid receptor antagonists naltrexone (1 mg/kg, s.c.), naloxone (1 mg/kg, s.c.), M8008 (16S-methylcyprenorphine; 1 mg/kg, s.c.) and MR 2266 (5,9-diethyl-2-(3-furylmethyl)2'-hydroxy-7,7-benzomorphan; 1 mg/kg) but not by naloxone methylbromide (1 mg/kg, s.c.), naloxone methyliodide (1 mg/kg, s.c.), naltrindole (1 mg/kg, s.c.), DIPPA (2-(3,4-dichlorophenyl)-N-methyl-N-[1S)-1-(3-isothiocyanatophenyl)-2-(1- pyrrolidinyl)-ethyl]acetamide; 3 mg/kg, i.p.) or naloxonazine (35 mg/kg, i.p.). This indicates an involvement of mu2-opioid receptors within the brain to mediate the anti-emetic effect of fentanyl. In other studies, naloxone 10-60 mg/kg, s.c. induced dose-related emesis but naltrexone was only emetic at 60 mg/kg, s.c. and naloxone methylbromide failed to induce emesis at doses up to 60 mg/kg, s.c. The emesis induced by a high dose of naloxone 60 mg/kg, s.c. was antagonized by CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine; 3-30 mg/kg, i.p.), 8-OH-DPAT, ((+/-)-8-hydroxy-dipropylaminotetralin; 0.003-0.3 mg/kg, s.c.), buspirone (3 mg/kg, s.c.) and fluphenazine (1-3 mg/kg, i.p.) but not by naltrexone (1-30 mg/kg, s.c.), metoclopramide (0.3-3 mg/kg, i.p.), sulpiride (0.3-3 mg/kg, i.p.), domperidone (0.1-3 mg/kg, i.p.), ondansetron (0.3-3 mg/kg, i.p.), granisetron (0.3-3 mg/kg, i.p.), scopolamine (0.3-3 mg/kg, i.p.) or promethazine (0.3-3 mg/kg, i.p.). The data is discussed in relation to opioid receptor mechanisms moderating emesis and the identification of potential sites of drug action available to inhibit the emetic reflex.

Inhibition of emesis by tachykinin NK1 receptor antagonists in Suncus murinus (house musk shrew).

The anti-emetic potential of CP-122,721 ((+)-2S,3S)-3-(2-methoxy-5-trifluoromethoxybenzyl)amino-2-phenylpi peridine), CP-99,994 ((+)-(2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine), CP-100,263 ((-)-(2R,3R)-3-(2-methoxybenzylamino)-2-phenylpiperidine), RP 67580 ((3R, 7aR)-7,7-diphenyl-2-[1-imino-2-(2-methoxyphenyl)ethyl] po-hydroisoindol-4-one), FK 888 (N2-[(4R)-4-hydroxy-1-(1-methyl-1H-in-dole-3-yl)carbonyl-L-propyl] -N-methyl-N-phenylmethyl-1-3-(2-naphthyl)-alaninamide) and GR 82334 ([D-Pro9[spiro-g-lactam]Leu10]-physalaemin-(1-11)) was investigated to inhibit nicotine (5 mg/kg, s.c.)-, copper sulphate pentahydrate (120 mg/kg, intragastric)- and motion (4 cm horizontal displacement at 1 Hz for 5 min)-induced emesis in Suncus murinus. A 30 min intraperitoneal pre-treatment with CP-122,721, CP-99,994, RP 67580 and FK 888 significantly (P < 0.05) antagonized nicotine-induced emesis with ID50 values of 2.1, 2.3, 13.5 and 19.2 mg/kg, respectively CP-100,263, the less active enantiomer of CP-99,994, was inactive at doses up to 10 mg/kg. Infusion of GR 82334, CP-122,721, CP-99,994 and FK 888 into the dorsal vagal complex of the hindbrain also antagonized nicotine-induced emesis yielding ID50 values of 1.1, 3.0, 3.3 and 58.0 microg/dorsal vagal complex, respectively RP 67580 and CP-100,263 were inactive. RP 67580 and FK 888 failed to antagonize copper sulphate-induced emesis but CP-122,721 and CP-99,994 were active yielding ID50 values of 2.2 and 3.0 mg/kg, i.p., respectively. CP-99,994 also completely prevented motion-induced emesis at 10 mg/kg, i.p. (P < 0.05) and RP 67580 produced a significant reduction of motion-induced emesis at 10 mg/kg, i.p. (P < 0.05). These studies provide evidence of a central site of action of tachykinin NK1 receptor antagonists to inhibit nicotine-induced emesis in S. murinus and confirm the broad profile of inhibitory action. The rank order of potency of the antagonists following the intra-dorsal vagal complex administration suggests that the S. murinus tachykinin NK1 receptor has a unique pharmacological profile.

5-HT3 receptors are not involved in conditioned taste aversions induced by 5-hydroxytryptamine, ipecacuanha or cisplatin.

We have used the rat to examine the involvement of the 5-HT3 receptor in the mechanism(s) of conditioned taste aversion induced by 5-hydroxytryptamine (5-HT) and selected emetic drugs. 5-HT, ipecacuanha and cisplatin all induced conditioned taste aversion at doses known to induce emesis in other species but the responses were resistant to treatment with the 5-HT3 receptor antagonists ondansetron and granisetron. Further, m-chlorophenylbiguanide, a selective and potent 5-HT3 receptor agonist, failed to induce a conditioned taste aversion. The data provide strong evidence that the 5-HT3 receptor is not involved in conditioned taste aversion mechanisms in the rat. Results are discussed in terms of the usefulness of the rat conditioned taste aversion paradigm to anti-emetic research.

Preliminary study on the antinociceptive effect of elephant beta-endorphin.

1. Intraventricular administration of human beta-endorphin and elephant beta-endorphin significantly prolonged the tail flick response tested 30 min later. However, elephant beta-endorphin was about 7-8 times more potent than human beta-endorphin in the tail flick test. 2. beta-Endorphin antagonized the antinociceptive effect of both human beta-endorphin and elephant beta-endorphin by the same extent. Naloxone also antagonized the antinociceptive effects of the beta-endorphins but it was less effective than beta-endorphin. 3. Human beta-endorphin and elephant beta-endorphin were of equal potency in inhibiting the abdominal constriction response induced by intraperitoneal (i.p.) acetic acid. Both beta-endorphin and naloxone antagonized these effects of the beta-endorphins with naloxone being more effective. 4. The present study showed that different opioid receptor subtypes may be involved in the tail flick test and the abdominal constriction test. Furthermore, elephant beta-endorphin was a better antinociceptive agent than human beta-endorphin in the tail flick test.

Disposition of ethmozine in cerebrospinal fluid and plasma of rabbits.

The concentration-time profiles of ethmozine, a newly introduced anti-arrhythmic drug, in the cerebrospinal fluid (CSF) and plasma of six rabbits (New Zealand white rabbits of both sexes, 4.0-5.0 Kg) were studied after intravenous bolus administration. CSF samples at various intervals were obtained while the animal was lightly anaesthetized with intravenous thiopentone (40 mg Kg-1) and blood samples at other intervals were taken while the animal was conscious. Blood samples (1 ml) were collected from the implanted cannula of the ear artery while CSF samples (0.3 ml) were obtained from the cisterna magna. The plasma concentrations of ethmozine in six rabbits declined rapidly after intravenous injection for up to 30 min. then slowly over 12 h. Using non-compartmental analysis, the mean (+/- S.E.M.) elimination half-life, mean residence time, plasma clearance and volume of distribution at steady state were 13.9 +/- 9.2 h, 19.9 +/- 13.4 h, 2.3 Lh-1 and 26.8 +/- 7.9 L respectively. The mean CSF-plasma concentration ratios for ethmozine at 0.5, 1.0, 2.0, 4.0, 8.0 and 12.0 h were 0.17, 0.14, 0.16, 0.16, 0.23 and 0.22 respectively. The results suggest that ethmozine is able to penetrate into the CSF from the general circulation and this may be related to its adverse effects on the central nervous system.

The effect of quaternary naloxone on the increased naloxone potency induced by morphine.

Using the abdominal constriction test in mice it was shown that the antinociceptive effect of morphine was inhibited by naloxone hydrochloride and its quaternary derivative naloxone methylbromide which presumably only acts peripherally. Pretreatment with a single dose of morphine 2.0 mg/kg s.c. did not alter the antinociceptive effect of a second dose of morphine given 3 h later. However, the antagonistic effect of naloxone against morphine was enhanced at this time. The development of increased naloxone potency was inhibited when naloxone hydrochloride was given together with morphine in the pretreatment. A similar inhibitory effect was observed when the quaternary derivative naloxone methylbromide was used instead of naloxone hydrochloride in the pretreatment regime. As there was no difference between the effects of naloxone hydrochloride and naloxone methylbromide in suppressing the development of increased naloxone potency induced by morphine pretreatment, it was concluded that this phenomenon may be mediated mainly through peripheral opiate receptors.

Rat hepatic prolactin receptor: pubertal exposure to sex steroids alters responsivity to testosterone.

Administration of testosterone enanthate to adult female rats lowered the level of hepatic prolactin receptor. Pubertal exposure of intact female rats to testosterone enanthate at the dose used did not affect the level of hepatic prolactin receptor in adults. However, the responsivity of such treated rats to testosterone challenge in adulthood was enhanced. Prepubertal ovariectomy of female rats lowered the level of hepatic prolactin receptor in adulthood. Exposure of the ovariectomized rats during puberty to mestranol (ethynylestradiol 3-methyl ether) at the dose used did not restore the normal adult female rat's level of hepatic prolactin receptor. However, they did become more resistant to subsequent testosterone challenge in adulthood. Exposure of prepubescent ovariectomized rats to testosterone enanthate during puberty reduced the already diminished level of hepatic prolactin receptor further. In addition, these rats were rendered more responsive to testosterone challenge in adulthood.

Increased naloxone potency induced by pretreatment with morphine and nalbuphine in mice.

Both morphine and nalbuphine were effective in suppressing the abdominal constriction response induced by intraperitoneal injection of acetic acid in mice. On a weight to weight basis, nalbuphine was more potent than morphine in this test. However, the effect of nalbuphine was more effectively blocked by naloxone. Pretreatment with morphine 2.0 mg/kg subcutaneously did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later. However, naloxone was about 1.4-fold more effective in antagonizing the antinociceptive effect of both drugs in morphine-pretreated mice than in saline-pretreated animals. Pretreatment with nalbuphine (1.0-2.0 mg/kg s.c.) did not alter the antinociceptive effect of either morphine or nalbuphine measured 3 h later, while naloxone effect was more effective in antagonizing the antinociceptive actions of morphine and nalbuphine. The increases in naloxone potency in antagonizing morphine after nalbuphine pretreatment were not dose-dependent on the amount of nalbuphine in the pretreatment and they were only marginally significant. In addition, these increases were much lower than that induced by morphine pretreatment. On the other hand, the naloxone effectiveness against nalbuphine itself was enhanced to a greater extent than that induced by morphine pretreatment. Furthermore, these increases in naloxone potency showed a dose-dependent relationship to the amount of nalbuphine used in the pretreatment. Based on these results, it was concluded that nalbuphine is an analgesic drug with properties in between those of the full agonist morphine and the partial agonist pentazocine.

The effect of chlorpromazine pretreatment on morphine analgesia and naloxone potency in adrenalectomized mice.

1. Morphine pretreatment (2.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 3 h later, but enhanced the antagonistic potency of naloxone. 2. Pretreatment with chlorpromazine slightly potentiated the antinociceptive effect of morphine measured 3.5 h later. The antagonistic effect of naloxone was also enhanced. 3. The observed effect of chlorpromazine on naloxone potency was augmented when naloxone was administered in the pretreatment regime. 4. The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 h before the morphine pretreatment. 5. Adrenalectomy sensitized the animals to the antinociceptive effect of morphine. However, the naloxone potency was similar to that of the sham-operated controls. 6. Adrenalectomy greatly attenuated the effect of chlorpromazine pretreatment on naloxone potency. However, the effect of combined pretreatment with either chlorpromazine plus naloxone or morphine remained unaffected. 7. These results indicate that the increased naloxone potency after chlorpromazine pretreatment may be partly mediated through an adrenal-linked process. However, it appears that this process is not essential for the development of increased naloxone potency induced by morphine pretreatment and for the interaction between chlorpromazine, naloxone and morphine.

The effect of chlorpromazine pretreatment on the narcotic antagonistic potency of naloxone in mice.

1. Morphine pretreatment (8.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 4 h later, but enhanced by the antagonistic potency of naloxone. 2. Pretreatment with chlorpromazine hydrochloride (0.5 2.0 mg/kg s.c.) potentiated the antinociceptive effect of morphine measured 4.5 h later. The antagonistic effect of naloxone was also enhanced. 3. The observed effect of chlorpromazine on naloxone potency was augmented when naloxone hydrochloride 0.2 mg/kg was administered in the pretreatment regime. 4. The enhanced naloxone potency induced by morphine pretreatment was inhibited by chlorpromazine administered 0.5 hr before the morphine pretreatment. 5. These results indicate that pretreatment with either morphine or chlorpromazine increased the antagonistic potency of naloxone. However, it appears that these two drugs act by different mechanisms.

The effect of adrenalectomy on the development of morphine tolerance and physical dependence in mice.

1. A molecular sieve morphine pellet implanted for 24 h induced measurable tolerance and physical dependence in mice. 2. Adrenalectomy sensitized the animals to the antinociceptive effective of morphine. However, the degree of tolerance induced by morphine pellet implantation was not significantly affected. 3. Quantitative assessment of naloxone-precipitated withdrawal symptoms showed that adrenalectomy slightly enhanced the development of physical dependence. 4. These results indicate that adrenalectomy has no effect on the rate of development of morphine tolerance but may be involved in the development of physical dependence.

The effect of prostaglandin E2 on increased naloxone potency induced by morphine pretreatment.

Pretreatment with prostaglandin E2 caused an increase in naloxone potency while the antinociceptive effect of morphine remained unaffected. These effects of prostaglandin E2 were not blocked by concomitant administration of naloxone in the pretreatment. Furthermore, when prostaglandin E2 was given together with morphine as pretreatment, the resulting naloxone antagonism measured was higher than those induced by pretreatment with the individual drugs. It is suggested that the induction of increased naloxone potency is likely to be mediated through a prostaglandin-linked process.

Effects of aspirin and paracetamol on naloxone reversal of morphine-induced inhibition of gastrointestinal propulsion in mice.

In mice, morphine caused a dose-dependent slowing of the rate of intestinal transit of a charcoal meal. This inhibitory effect of morphine was antagonised by naloxone. Pretreatment with a single dose of morphine did not induce any detectable tolerance to the inhibitory action of a second dose of morphine given 4 h later. However, naloxone was more effective in antagonising intestinal inhibition by morphine in morphine-pretreated mice than in saline-pretreated animals. Pretreatment with either aspirin or paracetamol did not alter the inhibitory action of morphine given 4.5 h later. However, the antagonistic effect of naloxone was significantly augmented, though not to the same extent as that caused by morphine pretreatment. When either aspirin or paracetamol was given together with morphine as pretreatment, the resulting naloxone antagonism measured 4 h later was significantly higher than that induced by pretreatment with the individual drugs. Furthermore, combined pretreatment with aspirin 20.0 mg/kg and morphine 40.0 mg/kg induced detectable tolerance to the inhibitory effect of a second dose of morphine given 4 h later. The present study indicates that prostaglandins reduce the naloxone antagonism of the inhibitory action of morphine on the rate of intestinal transit in mice and may interfere with the development of morphine tolerance.

The effect of aspirin and paracetamol on the increased naloxone potency induced by morphine pretreatment.

Using the abdominal constriction test in mice, it was shown that pretreatment with a single dose of morphine given 3 h previously caused a marked increase in the antagonistic effect of naloxone without any change in the antinociceptive action of morphine itself. Pretreatment with either paracetamol (10.0-20.0 mg/kg, s.c.) or aspirin (5.0-10.0 mg/kg, s.c.) caused a small but significant antagonism of the antinociceptive effect of morphine, while the antagonistic action of naloxone remained unaffected. However, when aspirin or paracetamol was administered with morphine in the pretreatment regime, the ability of morphine to induce an increase in naloxone potency was much attenuated. This inhibitory effect was dependent on the dose of aspirin or paracetamol used in the pretreatment regime. The antinociceptive effect of aspirin and paracetamol was also studied. In the doses used, they did have a mild antinociceptive effect, but the analgesic effect of morphine was not affected by the administration of these drugs 30 min beforehand. It is suggested that the antinociceptive effect of morphine is probably not dependent on prostaglandin, but that the induction of increased naloxone potency is likely to be mediated through prostaglandin synthesis.

Effect of morphine and naloxone on intestinal transit in mice.

Morphine caused a dose-dependent slowing of the rate of intestinal transit in mice. This inhibitory effect of morphine was antagonised by naloxone administration. Pretreatment with a single dose of morphine did not induce any detectable tolerance to the inhibitory effect of a second dose of morphine given 5 h later. However, naloxone was more effective in antagonising this inhibitory effect of morphine in morphine-pretreated mice than in saline-pretreated animals. Molecular sieve morphine pellet implantation for 24 h induced detectable tolerance to the inhibitory effect of morphine administered 3 h after removal of the pellet. In addition, the antagonistic effect of naloxone was also augmented when compared with blank pellet-implanted control animals. The present study has shown that the enhanced naloxone potency against the inhibitory effect of morphine was intestinal transit was observalbe before the development of overt tolerance, and that tolerance to the effect of morphine on the small intestine could be induced by implantation of a molecular sieve morphine pellet for 24 h.

Preliminary studies on increased naloxone potency and its relationship to morphine tolerance and dependence in mice.

1. Morphine pretreatment (8.0 mg/kg s.c.) induced no overt tolerance to its antinociceptive effect in mice 4 h later, but enhanced the antagonistic potency of naloxone. 2. A molecular sieve morphine pellet implanted for 24 h induced measurable tolerance, but the relative potency of naloxone was not significantly different from that observed after single-dose morphine pretreatment. The development of tolerance and increased naloxone potency do not, therefore, run parallel. 3. Naloxone-precipitated withdrawal symptoms were observed after single-dose morphine and after pellet implantation. However, molecular sieve morphine pellet implantation induced a higher degree of dependence as compared with single dose morphine pretreatment. 4. These results indicate that the rate of development of increased naloxone potency and of morphine tolerance and dependence do not run parallel. This implies that caution must be exercised in regarding increased naloxone potency as a sensitive indicator of the initiation and development of tolerance and dependence to morphine.

The effect of phenobarbitone pretreatment on the narcotic antagonistic potency of naloxone in mice.

Pretreatment with phenobarbitone (5.0-20.0 mg/kg, s.c.) did not alter the antinociceptive effect (tail-flick assay) of morphine measured 4.5 h later. However, naloxone was more potent in antagonising this antinociceptive effect in phenobarbitone-pretreated mice than in saline-retreated animals. Concomitant administration of naloxone in the pretreatment regime did not alter the effect of phenobarbitone. The enhanced naloxone potency was related to the amount of phenobarbitone given, and was observable at 3.0 and 4.5 h after pretreatment. It was no longer apparent at 6.0 h. Because of a difference in time course and in the ability of naloxone to block the phenomenon, it is suggested that the mechanisms underlying the increase in naloxone potency induced by phenobarbitone pretreatment and morphine pretreatment may not be the same.