Capsaicin pretreatment interferes with the thermoregulatory effect of morphine

Body temperature changes after the administration of 8 mg/kg morphine sulphate were studied in freely-moving and restrained rats, which were pretreated with capsaicin (300 mg/kg). Morphine caused a hyperthermic response irrespective of the previous capsaicin treatment in freely-moving rats; the lag time from the application of morphine to the hyperthermic maximum was, however, significantly delayed in capsaicin pretreated rats. A careful habituation to the experimental procedure (including injections, taking temperature, etc.) facilitated the hyperthermic response both in the pretreated and the control groups. Restrained rats typically showed a hypothermic response to the same dose of morphine. The drop of body temperature in habituated animals was significantly larger in the case of capsaicin pretreated rats. This potentiation of the hypothermic effect of morphine can be regarded as the primary site of interaction between capsaicin and morphine. Since capsaicin pretreated rats also showed an exaggerated thermoregulatory response to experimental stress, we conclude that the thermoregulatory effects of morphine and endogenous opiates are facilitated after capsaicin pretreatment.     

The effects of peptides on tolerance to the cataleptic and hypothermic effects of morphine in the rat

The effects of melanotropin release inhibiting factor (MIF) and a cyclic analog, cycio (Leu-Gly) derived from MIF on the development of tolerance to the cataleptic and hypothermic effects of morphine in the rat were investigated. The rats were made tolerant to morphine by the subcutaneous implantation of four morphine pellets over a 3-day period. Each pellet contained 75 mg of morphine-free base. Following morphine pellet implantation, tolerance developed to the cataleptic and hypothermic effects of morphine. A dose of morphine (50 mg/kg) which produced hypothermia in placebo-pelleted rats, produced hyperthermia in morphine-pelleted rats. Administration of MIF and cycio (Leu-Gly) prior to and during morphine pellet implantation inhibited the development of tolerance to the cataleptic effect of morphine. Similarly the hyperthermic effect of morphine in morphine-tolerant rats was prevented by both the peptides. Previously, the present authors reported Ithat these peptides also inhibited tolerance to the analgesic effect of morphine. It is concluded that tolerance to analgesic, cataleptic and hypothermic effects of morphine may share common features in its genesis.     

Effect of kappa-opioid receptor agonists on morphine analgesia in morphine-naive and morphine-tolerant rats

The effect of i.p. administration of kappa-opioid receptor agonists, bremazocine, tifluadom and U-50,488H on morphine (8 mg/kg i.p.)-induced analgesia in morphine-naive and morphine tolerant male Sprague-Dawley rats was determined using the tail-flick test. The tolerance to morphine in the rats was induced by s.c., implantation of six morphine pellets during a 7-day period. Implantation of morphine pellets resulted in the development of tolerance as evidenced by the decrease in the analgesic response to morphine when compared to placebo pellets implanted rats. Bremazocine (0.3, 1.0 and 3.0 mg/kg) and U-50,488H (16 mg/kg) antagonized morphine-induced analgesia in morphine-naive rats while tifluadom (8 and 16 mg/kg) potentiated the effect. In morphine-tolerant rats, bremazocine (3 mg/kg) and U-50,488H (16 mg/kg) potentiated morphine-induced analgesia. Tifluadom at any of the doses had no effect on morphine-induced analgesia in morphine-tolerant rats. These results provide evidence that different kappa-opioid agonists modify morphine-induced analgesia differentially in morphine-naive and morphine-tolerant rats.     

Variation in tolerance to the antinociceptive,hormonal and thermal effects of morphine after a 5-day pre-treatment of male rats with increasing doses of morphine

The manifestation of tolerance to the effects of morphine on nociception and the secretion of anterior pituitary hormones, and the correlation of hormonal effects to changes in body temperature and to hypothalamic monoamines were studied in male rats. Morphine (three times a day in increasing doses) or saline (control) were administered intraperitoneally during a 5-day treatment and either saline or morphine was administered as an acute challenge 92 h later. The influence of the thermal environment on the effect of morphine on the body temperature was also studied.The 5-day morphine regimen was sufficient for the development of tolerance to the antinociceptive effect of morphine. After a 92-h lag-time, the tolerance was still complete. Tolerance to the depressant effect of morphine (10–25 mg/kg) on cold-stimulated TSH secretion was seen at 2 h, but was only barely detectable at 1 h, after the injection of a challenge dose. On the other hand, a tolerance to the stimulatory effect of morphine on prolactin secretion was already seen 1 h after the acute dose of morphine. Tolerance to the hypothermic effect of morphine (25 mg/kg) was evident in rats kept at +4°C after the challenge dose. On the contrary, no tolerance to the hyperthermic effect of morphine (15 or 25 mg/kg) was observed in rats kept at +30°C. However, the hyperthermia was reversed when these rats were moved to +4°C for 30 min, irrespective of whether they were morphine pretreated or not. Thus the removal of the hyperthermic stimulus decreased the core temperature of all rats.We conclude, that with a 5-day morphine regimen and a 4-day lag time, tolerance developed to the antinociceptive, hypothermic and some hormonal effects of mor phine but not to its hyperthermic effect or to its effects on hypothalamic 5-HIAA concentrations. Neither the changes in the rectal temperature nor the minor alterations in the concentrations of the hypothalamic amine neurotransmitters correlated with the manifestation of tolerance to the cold-stimulated TSH secretion. Correspondence to: P. T. Mannisto at the above address     

Tolerance to hyperthermia produced by morphine in rat

The present study addressed the prevailing notion that the rat develops tolerance only to the hypothermic effect of morphine and not to its hyperthermic effect. Rectal temperatures were measured at different intervals after various test doses of morphine in rats that had been rendered tolerant to morphine antinociception, by daily intraperitoneal injections of 0, 20, or 200 mg/kg morphine, and dependent, as seen by naloxone-produced loss of body weight. The well-known tolerance to the hypothermic effect was confirmed by changes in the dose-response curves for latency to peak hyperthermic response. In the falling arm of the test dose time/effect curve, consistent, clear decreases in morphine hyperthermia were seen. These decreases were proportional to the chronic treatment dose, and occurred in a normal test environment, where acute hypothermic effects were produced by morphine at short test intervals, and in a warm test environment, where no hypothermia was seen. Similar effects were noted when the data were analyzed in terms of area under the time/effect curve for hyperthermia. In the morphine-treated animals, decreased hyperthermia was seen despite serum morphine levels at the time of testing being up to twice as high as those in control rats. It was concluded that substantial tolerance develops to hyperthermia produced by opiates in rats. The previous difficulty in seeing this effect is discussed in regard to the probability that, in naive rats, the effect of morphine shortly after administration of a test dose reflects a summation of two opposing, acute thermic effects. The findings challenge the view that tolerance develops only to the depressant, and not to the excitatory, effects of opiates.     

Role of 5-hydroxytryptamine in morphine-, pethidine-, and methadone-induced hypothermia in rats at low ambient and room temperature.

1 The effect of morphine (10 or 20 mg/kg s.c.), pethidine (25 or 50 mg/kg s.c.) or methadone (4 or 8 mg/kg s.c.) on the body temperature of nontreated and p-chlorophenylalanine-pretreated rats was studied at room (21+/-0.2 degrees C) or low ambient (12+/-0.2 degrees C) temperature. 2 Neither pethidine nor smaller doses of morphine and methadone altered the mean rectal temperature of rats kept at room temperature but larger doses of morphine and methadone produced significant hypothermia. 3 All narcotic analgesics at doses used in the present investigation produced significant hypothermia in rats maintained in a low ambient temperature. The hypothermia was prevented by naloxone (1 mg/kg s.c.). 4 The administration of p-chlorophenylalanine (PCPA, 320 mg/kg i.p.) 48 h before the narcotic injection prevented the fall in body temperature both at room and low ambient temperature. 5 The administration of narcotic analgesics at doses, which when administered by themselves did not alter the body temperature of rats, produced significant hyperthermia in rats pretreated with PCPA. 6 When rats pretreated with PCPA were given 5-hydroxytryptophan (75 mg/kg s.c.) 30 min before narcotic administration, the usual response to narcotics was restored. 7 It appears that pethidine and methadone as well as morphine have both hyperthermic and hypothermic actions in rats and that 5-hydroxytryptamine may be involved in the narcotic-induced hypothermia not only at room temperature but also at low ambient temperature.     

Effects of morphine in rats treated chronically with U-50,488 H, a kappa opioid receptor agonist

The pharmacological effects of morphine, namely analgesic, hyperthermic and cataleptic effects, were assessed in rats rendered tolerant to U-50,488H, a kappa opioid receptor agonist. Male Sprague-Dawley rats were injected intraperitoneally with U-50,488H (25 mg/kg) twice a day for four days. The rats which served as controls were injected similarly with the vehicle. Chronic administration of U-50,488H resulted in the development of tolerance to its analgesic and hypothermic effects, but not to its diuretic effect. The development of tolerance to the pharmacological effects of U-50,488H was associated with decreased binding of [3H]ethylketocyclazocine [( 3H]EKC) to brain and spinal cord membranes. The decreased binding of [3H]EKC in U-50,488H-treated rats was due to changes in the Bmax value; the Kd values remained unaltered. Intraperitoneal administration of morphine (8 mg/kg) to rats produced analgesia (as determined by the tail-flick test) and hyperthermia. A dose of 50 mg/kg of morphine produced cataleptic response. The intensity of analgesic, hyperthermic and cataleptic effects of morphine were unaltered in rats tolerant to U-50,488H. The development of tolerance to analgesic and hypothermic effects of U-50,488H were associated with down-regulation of brain and spinal cord kappa opioid receptors. Finally, U-50,488H does not confer cross-tolerance to morphine, a predominantly mu opioid receptor agonist.     

Cross-tolerance between ethanol and morphine with respect to their hypothermic effects

Daily administration of ethanol (10-12 g/kg) to rats in a liquid diet resulted in tolerance to the hypothermic effects of ethanol. The rats also developed cross-tolerance to the hypothermic effect of morphine (15 and 30 mg/kg), whereas no cross-tolerance to the hyperthermic effect of morphine (5 mg/kg) was seen. Administration of morphine (30 mg/kg i.p.) for 3 days resulted in tolerance to morphine hypothermia and also cross-tolerance to ethanol-induced hypothermia. These studies fit with our hypothesis that tolerance and cross-tolerance among drugs develop to drug effects rather than to the drug per se. Therefore drugs sharing a common effect, even by different mechanisms, might show cross-tolerance for that effect.     

Alpha-fluoromethylhistidine decreases the Leu-enkephalinamide- and morphine-induced corticosterone response in rats.

The effect of inhibition of brain histamine synthesis by alpha-fluoromethylhistidine (alpha-FMH) on the pituitary adrenocortical activity stimulated by D-Ala-D-Leu-enkephalinamide (DADL) and morphine was investigated indirectly through corticosterone secretion in conscious rats. alpha-FMH (20 mg/kg i.p.) drastically reduced the whole brain histamine content, measured 2 h later. The same pretreatment also considerably reduced the corticosterone response to morphine given intraperitoneally. When alpha-FMH was administered intracerebroventricularly (50 micrograms), the maximum inhibition of the corticosterone response to DADL and morphine occurred 4 h after administration, which may suggest a weaker accessibility of alpha-FMH from the cerebral ventricle to the brain structures involved in pituitary-adrenocortical stimulation. The corticosterone responses were not related to the core temperature changes. These results indicate that inhibition of brain histamine synthesis by alpha-FMH considerably impairs the pituitary-adrenocortical response to the opioid delta- and mu-receptor agonists DADL and morphine. They also suggest that neuronal histamine is significantly involved in the central stimulation of the pituitary-adrenal axis by opioids.     

Naloxone produces hypothermia in rats pretreated with beta-endorphin and morphine

The effects of naloxone (an antagonist of opioids at opiate receptors) on the thermoregulatory responses were assessed in three groups of naive (saline-treated), morphine-tolerant (24 hr after a dose of 100 mg/kg (s.c.) of morphine-oil suspension or three doses of 100 mg/kg (i.p.) of morphine and beta-endorphin-tolerant (24 hr after an intraventricular dose of 100 μg of beta-endorphin) rats at an ambient temperature of 22°C. Both morphine and beta-endorphin produced hypothermia, catatonia and sedation in naive rats. The hypothermia was due to decreased metabolic rate and cutaneous vasodilation. However, both in morphine-tolerant and beta-endorphin-tolerant rats, morphine and betaendorphin each produced hyperthermia rather than hypothermia. There were no changes in behavior. The hyperthermia was due to increased metabolism. Furthermore, naloxone administration produced a dose-dependent hypothermia and abstinence syndrome in both morphine-tolerant and beta-endorphin-tolerant rats, but not in naive rats. The hypothermia in response to naloxone in opioid-tolerant rats was brought about by both decreased metabolism and cutaneous vasodilatation. The data indicate that pretreatment of rats with opioids alters the thermoregulatory effects of naloxone.     

Studies on the possible role of pharmacokinetics in the development of tolerance to morphine in the rat.

1. The possible role of pharmacokinetics of morphine in the development of tolerance to the analgesic and hyperthermic effects of morphine was studied in the rat. 2. Male Sprague-Dawley rats were made tolerant to morphine by implanting 6 morphine pellets each containing 75 mg of morphine base for 7 days. The assessment of the degree of tolerance to morphine and pharmacokinetic parameters were done 72 hr after pellet removal. 3. Tolerance developed to both the analgesic and hyperthermic effects of morphine as evidenced by decreased responses to morphine in morphine pellet implanted rats compared with placebo pellet implanted rats. 4. The pharmacokinetic parameters, AUC0-->infinity, Cmax, t1/2, k, MRT, Vss and Clt were determined after injecting 5 and 10 mg/kg doses of morphine intravenously to placebo and morphine pellet implanted rats and using a highly sensitive and specific RIA method to quantitate serum levels of morphine. For a 5 mg/kg dose of morphine, the AUC0-->infinity and t1/2 in morphine pellet implanted rats were significantly higher than in placebo pellet implanted rats, but the k value was lower. The other pharmacokinetic parameters for morphine in the two treatment groups did not differ. For 10 mg/kg dose, the only change was an increase in the MRT in morphine tolerant rats when compared to nontolerant rats. 5. The results establish that the development of tolerance to the analgesic and hyperthermic effects of morphine is not related to pharmacokinetics of morphine in serum but may be related to modification of receptor systems in the central nervous system.     

Role of brain catecholamines and 5-hydroxytryptamine in morphine induced temperature changes in normal and tolerant rats and mice

Summary Morphine (5–20 mg/kg) produced hyperthermia in normal, unrestrained rats. Rats which were chronically treated with morphine became tolerant and physically dependent but did not develop tolerance to the acute hyperthermia. Pretreatment of rats with 6-hydroxydopamine to deplete brain catecholamines potentiated the acute morphine hyperthermia in normal rats but not in tolerant rats. The effect is probably related to brain dopamine. Depletion of brain 5-hydroxytryptamine (5-HT) produced by 5,6-dihydroxytryptamine pretreatment, antagonized the acute morphine hyperthermia in both normal and tolerant rats. Morphine (5–20 mg/kg) produced hypothermia in both normal and morphine tolerant mice. Pretreatment of normal mice with 6-hydroxydopamine depleted brain noradrenaline and dopamine and antagonized the hypothermia. Pretreatment with pargyline and 6-hydroxydopamine caused a greater loss of cerebral dopamine than 6-hydroxydopamine alone and resulted in an acute morphine hyperthermia. Morphine also caused hyperthermia when given to tolerant mice pretreated with 6-hydroxydopamine. Pretreatment of normal mice with 5,6-dihydroxytryptamine totally abolished the acute morphine hypothermia. In tolerant mice treated with 5,6-dihydroxytryptamine morphine caused a rise in temperature. It is concluded that (1) a single dose of morphine given to normal rats shifts a hypothalamic 5-HT: dopamine balance in favour of 5-HT; (2) activation of a 5-HT mechanism causes hyperthermia whereas dopamine mediates hypothermia; (3) rats chronically treated with morphine do not become tolerant to the acute hyperthermia because morphine tolerance has little effect on 5-HT; (4) brain dopamine mechanisms readily develop tolerance to morphine; (5) the hypothermia produced by a single dose of morphine in normal mice is mediated by dopamine and, to a lesser extent, 5-HT mechanisms; (6) the hypothermic mechanisms rapidly develop tolerance to morphine; (7) loss of cerebral dopamine and 5-HT in morphine tolerant mice leads to an acute morphine hyperthermia due to another neurotransmitter.     

The effect of cholinergic antagonists on increases of spontaneous locomotor activity and body weight induced by the administration of morphine to tolerant rats

Increases both in spontaneous locomotor activity and in body weight were observed after the administration of morphine-HCl (100 mg/kg, i. p.) to tolerant rats. These signs were inhibited by pretreatment of the morphine-tolerant rats with cholinergic antagonists; the inhibition by scopolamine was greater than that by methscopolamine or atropine. These results suggest that both central and peripheral cholinergic mechanisms participate in the increases both in spontaneous locomotor activity and in body weight of tolerant rats after morphine administration.Portions of this work were presented at the 42nd and 43rd meeting of Japanese Pharmacological Society in Kanto district, May 23, 1970 and October 24, 1970 and in Jap. J. Pharmacol. 20, 455–457 (1970), as a preliminary report.     

Potentiation of morphine hyperthermia in cats by pimozide and fluoxetine hydrochloride

Administration of morphine sulfate (1--4 mg/kg i.v.) to cats produces changes in body temperature, with hyperthermia appearing with larger doses. Since the central neurotransmitters dopamine and serotonin have been implicated in thermoregulation, studies were done to determine whether morphine's action could be mediated via these transmitters. Temperature responses were measured in freely moving cats by means of rectal thermometer probes. Either pimozide, 0.5 mg/kg i.p., a specific DA receptor blocker, or fluoxetine HCl, 10 mg/kg i.p., a specific inhibitor of 5-HT uptake, was administered 2--3 h prior to morphine injection. Temperatures were monitored for 3.5 h after morphine administration. Both agents were found to enhance the hyperthermic response to morphine with the maximum morphine effect occurring in most cases by 2 h. The results indicate that a balance in the ratio of 5-HT : DA may be involved in cat thermoregulation and that the hyperthermic response in the cat to morphine may be effected by shifting this 5-HT : DA ratio.     

Effects of morphine and nalorphine on kainic acid-induced hypothermia in rats

Intraventricular administration of kainic acid at the dose of 0.1 g induces a significant depression of rectal temperature followed rapidly by its slight elevation. Morphine (40.0 mg·kg^-1 IP), which by itself elicited biphasic effect on the body temperature of rats—initially hypothermia followed by hyperthermia—slightly increased the kainic acid-induced hypothermia. Kainic acid did not cause any changes in the hyperthermic effect of low doses of morphine (10.0 mg·kg^-1). Pretreatment of rats with nalorphine enhanced the kainic acid-induced hypothermia. On the contrary, nalorphine reversed the hypothermic effect produced by morphine at the dose of 40.0 mg·kg^-1. The results suggest that morphine and kainic acid-induced hypothermia are not mediated by the influence on the same type of receptors.     

Hyperthermic responses to central and peripheral injections of morphine sulphate in the cat

1 The effect of morphine on body temperature was studied in conscious, unrestrained cats provided with implanted third or lateral cerebral ventricular cannulae, jugular venous catheters and retroperitoneal thermocouples.

2 Intraventricular injections of 2.5-50 μg and intravenous injections of 1-10 mg/kg morphine sulphate produced dose-related hyperthermic responses. Similar mean increases in body temperature after administration of a given dose were elicited in cats which had not previously received morphine and, provided that tolerance was avoided by spacing injections at least 72 h apart, in cats which received a series of injections of morphine. Morphine was at least 850 times more potent when injected into the third ventricle than when given intravenously. Increasing the dose of morphine sulphate injected into the third ventricle to 1250 μg only prolonged the hyperthermia. Morphine did not produce hypothermia at any dose tested.

3 Injection of 10 μg morphine sulphate into the third ventricle produced similar hyperthermias at ambient temperatures (tas) of 4-6, 21-23 and 33-36°C. The increase in body temperature was associated with shivering at the lower tas. At the highest ta, shivering was not evoked, but respiratory rate decreased after morphine if it was initially elevated. These results suggest that morphine increased the level at which body temperature was regulated.

4 Neither metiamide nor indomethacin antagonized morphine so histamine and prostaglandins were apparently not required for the hyperthermic effect.

     

Peripheral and central opioid activity in the analgesic potency of morphine

The role of neural histamine in morphine-analgesia and in morphine-induced potentiation of stress analgesia was studied. Pretreatment of rats with alpha-fluoromethylhistidine (alpha-FMH) (200 micrograms i.c.v./rat; daily for five days) increased the analgesic potency of morphine, centrally or peripherally injected, in the tail-flick assay. This increase was significantly blocked by i.c.v. or i.p. beta-funaltrexamine (beta-FNA) a mu selective irreversible opioid receptor antagonist, whereas i.c.v. injected naltrexone did not block the increased analgesic potency of the i.c.v. morphine. Rats subjected to cold-restrained stress (60 min at 4 degrees C) showed increased tail-flick latency, compared to the unstressed group. The analgesic potency of morphine was significantly greater in rats subjected to restraint with respect to unstressed rats. However, the inhibition of histamine biosynthesis by alpha-FMH significantly reduced cold-restraint analgesia in controls, and also inhibited the analgesic efficacy of the opiate. These results indicate that neural histamine may be responsible for pain response modifications observed in rats subjected to cold-restraint conditions, and of morphine-potentiation of stress analgesia. The data also suggest a close association between increased analgesic potency of morphine and inhibition of histaminergic effects, possibly implying a functional supersensitivity and an increase in opioid receptors.     

Cross tolerance between ketamine and morphine to some pharmacological and biochemical effects

Whether morphine and ketamine induced cross-tolerance to some of their common pharmacological and biochemical effects, namely analgesia and enhancement of metabolites of dopamine (DA) in the striatum and limbic area of the rat was analysed. Ketamine was given at the dose of 100 mg/kg, twice a day for 8 days. After this treatment, a challenge dose of morphine (15 mg/kg, i.p.) still induced analgesia comparable to that induced by morphine alone, showing no cross-tolerance to this effect. In contrast, the challenge dose of morphine given to ketamine-tolerant rats no longer enhanced metabolism of DA, indicating the appearance of cross-tolerance to this effect. A high degree of tolerance to morphine was obtained after the subcutaneous implantation of rats with pellets of morphine; a challenge dose of ketamine to morphine-tolerant rats induced marked analgesia, with no cross-tolerance to this pharmacological effect, while cross-tolerance was present to the biochemical effect. The existence of a high degree of reciprocal cross-tolerance in both areas and on both metabolites of DA is consistent with the hypothesis of action at a common receptor; the lack of cross-tolerance to the analgesic effect indicates that analgesia is achieved by a different mechanism for the two drugs.     

Electroencephalographic and behavioral tolerance and cross-tolerance to morphine and methadone in the rat.

Electroencephalagraphic (EEG) and electromyographic activity recordings were collected continuously from female Sprague-Dawley rats made tolerant by chronic iv administration of either morphine (10 mg/kg/2 hr) or methadone (2 mg/kg/1.5 hr). The effects on the EEG and gross behavior of iv challenge doses of morphine (10, 20, and 40 mg/kg) and methadone (1, 2, and 4 mg/kg) in naive and tolerant rats were assessed. In naive rats, 2 and 4 mg/kg of methadone were equipotent with 10 and 20 mg/kg of morphine, respectively, with regard to the duration of the induced EEG slow burst activity and behavioral stupor. However, methadone was found to be relatively more potent, about 10 times as effective as morphine, in increasing the EEG voltage. Tolerance to these effects developed more quickly to morphine than to methadone. Using the degree of increase in integrated EEG voltage output, it was found that methadone-tolerant rats showed a high degree of cross-tolerance to morphine. On the other hand, morphine-tolerant rats demonstrated very low cross-tolerance to methadone. Thus, the differential tolerance and cross-tolerance to morphine and methadone found in this study may shed further light on the pharmacodynamics behind the reported high incidence of methadone-related toxicities among heroin-dependent individuals.     

A selective kappa-opioid agonist, U-50,488H, blocks the development of tolerance to morphine analgesia in rats

The development of tolerance to morphine analgesia was completely blocked by the coadministration of a selective kappa-opioid agonist, U-50,488H at doses of 3.2 or 10 mg/kg i.p. These doses of U-50,488H exerted no analgesic effect by themselves and did not affect the analgesia induced by 10 mg/kg of morphine. The analgesic effect of morphine was restored when 10 mg/kg of U-50,488H was coinjected in morphine-tolerant rats. These findings suggest that activation of the kappa-opioid system prevents the development of tolerance to morphine analgesia.