Hypothermic Effects Of Morphine Research Articles

Alterations in nociception and morphine antinociception in mice fed a high-fat diet

Currently, more than 78.6 million adults in the United States are obese. A majority of the patient population receiving treatment for pain symptoms is derived from this subpopulation. Environmental factors, including the increased availability of food high in fat and sugar, contribute to the continued rise in the rates of obesity. The focus of this study was to investigate whether long-term exposure to a high-fat, energy-dense diet enhances baseline thermal and inflammatory nociception while reducing sensitivity to morphine-induced antinociception. Antinociceptive and hypothermic responses to morphine were determined in male and female C57BL/6N mice fed either a “western-style” diet high in fat and sucrose (HED) or a standard low-fat chow diet for 15 weeks. Antinociception was assessed using both the hot plate and tail flick tests of acute thermal pain and the formalin test of inflammatory pain. Acute administration of morphine dose-dependently increased antinociception in the hot plate and tail flick assays for mice of both sexes fed chow and HED. However, female mice displayed lower antinociceptive response to morphine compared to males in the tail-flick test. Hypothermic responses to acute morphine were also assessed in mice fed chow or HED. Male and female mice fed chow, and female mice fed HED displayed similar hypothermic responses to morphine. However, males fed HED did not exhibit morphine-induced hypothermia. Tolerance to the antinociceptive and hypothermic effects of morphine was assessed after ten days of repeated daily administration (10mg/kg morphine). Male mice fed chow or HED developed tolerance to morphine in the hot plate test. However, females fed HED did not. In the tail flick assay, only mice fed HED developed tolerance to morphine. All groups showed tolerance to morphine-induced hypothermia. In the formalin test, we found that both male and female mice fed HED had reduced sensitivity to the antinociceptive effects of morphine (6mg/kg). Collectively, these data suggest that sensitivity and tolerance to the antinociceptive effects of morphine may be dependent on diet and sex in the hot plate and tail flick thermal pain models, and that the acute antinociceptive effects of morphine in the formalin inflammatory pain model may also be dependent on these two factors. In addition, diet and sex can influence morphine-induced hypothermia. Exposure to an HED may lead to changes in neuronal signaling pathways that alter nociceptive responses to noxious stimuli in a sex-specific manner. Thus, dietary modifications might be a useful way to impact pain therapy.

Tolerance to the antinociceptive and hypothermic effects of morphine is mediated by multiple isoforms of c-Jun N-terminal kinase.

The abuse and overdose of opioid drugs are growing public health problems worldwide. Although progress has been made toward understanding the mechanisms governing tolerance to opioids, the exact cellular machinery involved remains unclear. However, there is growing evidence to suggest that c-Jun N-terminal kinases (JNKs) play a major role in mu-opioid receptor regulation and morphine tolerance. In this study, we aimed to determine the potential roles of different JNK isoforms in the development of tolerance to the antinociceptive and hypothermic effects of morphine. We used the hot-plate and tail-flick tests for thermal pain to measure tolerance to the antinociceptive effects of once-daily subcutaneous injections with 10 mg/kg morphine. Body temperature was also measured to determine tolerance to the hypothermic effects of morphine. Tolerance to morphine was assessed in wild-type mice and compared with single knockout mice each lacking the JNK isoforms (JNK1, JNK2, or JNK3). We found that loss of each individual JNK isoform causes impairment in tolerance for the antinociceptive and hypothermic effects of daily morphine. However, disruption of JNK2 seems to have the most profound effect on morphine tolerance. These results indicate a clear role for JNK signaling pathways in morphine tolerance. This complements previous studies suggesting that the JNK2 isoform is required for morphine tolerance, but additionally presents novel data suggesting that additional JNK isoforms also contribute toward this process.

Morphine-induced antinociception and reward in "humanized" mice expressing the mu opioid receptor A118G polymorphism.

The rewarding and antinociceptive effects of opioids are mediated through the mu-opioid receptor. The A118G single nucleotide polymorphism in this receptor has been implicated in drug addiction and differences in pain response. Clinical and preclinical studies have found that the G allele is associated with increased heroin reward and self-administration, elevated post-operative pain, and reduced analgesic responsiveness to opioids. Male and female mice homozygous for the "humanized" 118AA or 118GG alleles were evaluated to test the hypothesis that 118GG mice are less sensitive to the rewarding and antinociceptive effects of morphine. We found that 118AA and 118GG mice of both genders developed conditioned place preference for morphine. All mice developed tolerance to the antinociceptive and hypothermic effects of morphine. However, morphine tolerance was not different between AA and GG mice. We also examined sensitivity to the antinociceptive and hypothermic effects of cumulative morphine doses. We found that 118GG mice show reduced hypothermic and antinociceptive responses on the hotplate for 10mg/kg morphine. Finally, we examined basal pain response and morphine-induced antinociception in the formalin test for inflammatory pain. We found no gender or genotype differences in either basal pain response or morphine-induced antinociception in the formalin test. Our data suggests that homozygous expression of the GG allele in mice blunts morphine-induced hypothermia and hotplate antinociception but does not alter morphine CPP, morphine tolerance, or basal inflammatory pain response.

Morphine-induced motor stimulation, motor incoordination, and hypothermia in adolescent and adult mice

Given evidence for age-related differences in the effects of drugs of abuse, surprisingly few preclinical studies have explored effects of opioids in adolescents (versus adults). This study compared the motor stimulating, ataxic, and hypothermic effects of morphine in adolescent, late adolescent, and adult mice. Plasma and brain levels of morphine were assessed to examine possible pharmacokinetic differences among the age groups. Locomotion was measured as occlusions of horizontal infrared light beams, ataxia as failing the horizontal wire test, body temperature by rectal probe, and morphine levels by HPLC-UV. Morphine (3.2-56 mg/kg, i.p.) increased locomotion along an inverted U-shaped dose-response curve in adolescent, late adolescent, and adult male C57BL/6J mice. Its potency to stimulate locomotion was similar in all age groups. However, maximal stimulation was higher in adolescents than in late adolescents, and higher in late adolescents than in adults. In contrast, adolescents showed less ataxia than adults when given morphine (5.6-100 mg/kg, i.p.). The hypothermic effects of morphine did not differ among the age groups. Morphine levels, which peaked in plasma at 15 min and in brain at 45 min after i.p. injection, did not show age-related differences. The finding that adolescents are not generally more sensitive to morphine than adults, but differ in their sensitivity to effects involving nigrostriatal/mesolimbic dopamine systems, is consistent with evidence of overactivity of these dopamine systems during adolescence relative to adulthood. The age-related differences observed here are unlikely due to pharmacokinetic factors.

Cold exposure attenuates effects of secretagogues on serum prolactin and growth hormone levels in male rats.

The stimulatory effect of morphine, dexmedetomidine (an alpha 2-adrenoceptor agonist), 1-(3-chlorophenyl)-piperazine (m-CPP, a 5-HT1B agonist), U-50488H (a kappa-opioid receptor agonist), pimozide (a dopamine antagonist), and restraint stress on prolactin and growth hormone (GH) secretion was compared during cold exposure (4 degrees C) and under basal conditions (30 degrees C) in male rats. Rectal temperature was also measured. The stimulatory effect of morphine, dexmedetomidine, m-CPP, and partially U-50488H on prolactin secretion was attenuated in rats kept at 4 degrees C. Cold exposure did not abolish prolactin release induced by pimozide and restraint stress. Cold exposure also antagonized the effect of morphine and dexmedetomidine on GH secretion. The stimulatory effect of morphine on prolactin and GH secretion was restored in the warm environment despite the sustained hypothermia. Cold exposure blocked the stimulatory effect of morphine on prolactin secretion in rats that were tolerant to the hypothermic effect of morphine. Thus hypothermia caused by morphine, dexmedetomidine, and m-CPP during cold exposure is not the sole factor in the antagonistic effect of cold. We suggest that cold exposure releases some compound(s) modulating hypothalamic neural pathways.

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 degrees 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 degrees C. However, the hyperthermia was reversed when these rats were moved to +4 degrees 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of naltrexone on the binding of [ 3H] D-Ala 2, MePhe 4, Gly-ol 5-enkephalin to brain regions and spinal cord and pharmacological responses to morphine in the rat

1. 1. The effects of naltrexone pellet implantation and removal on the analgesic and hypothermic effects of morphine and the binding of 3H- d-Ala 2, MePhe 4, Gly-ol 5-enkephalin (DAMGO) to μ-opiate receptors in rat brain regions and spinal cord were determined. 2. 2. Male Sprague-Dawley rats were implanted subcutaneously with a pellet containing 10 mg of naltrexone for 7 days. Placebo pellet implanted rats served as controls. The pellets were removed on day 8, and the analgesic and hyperthermic effects were determined in the rat 24 hr later. Morphine produced a dose-dependent analgesic and hyperthermic responses in rats implanted with placebo pellets. Enhanced analgesic and hyperthermic responses to morphine were produced in rats implanted with naltrexone pellets. 3. 3. The binding constants ( B max and K d values) of [ 3H]DAMGO in regions of the brain (amygdala, hypothalamus, striatum, midbrain, hippocampus, pons + medulla and cortex), and spinal cord of rats with naltrexone pellet left intact or removed were determined. The B max values of [ 3H]DAMGO were increased in all brain regions and spinal cord of rats in which the naltrexone pellets were left in place or removed prior to sacrificing. However, the K d values of [ 3H]DAMGO were unaffected by naltrexone treatment. 4. 4. It is concluded that enhanced analgesic and hyperthermic response to morphine is produced in rats implanted with naltrexone pellets and such alterations in the pharmacological responses are due to up-regulation of μ-opiate receptors in all the brain regions and spinal cord. Additionally whether the pellets were left intact (receptors blocked) or removed (receptors not blocked), the μ-opiate receptors were up-regulated in spinal cord and all the regions of the brain.

Effect of morphine during pregnancy and lactation in mice

The influence of pregnancy and lactation on morphine-induced hypothermia and hyperactivity was investigated in Rockland-Swiss mice. Pregnant mice were slower to recover from the hypothermic effect of morphine than nonpregnant controls. The greatest hypothermic response was seen in mice at day 18, the day before parturition. On the day after parturition, mice recovered faster from morphine-induced hypothermia than controls. During lactation, mice were again slower to recover from the morphine-induced hypothermia. Morphine-induced locomotor activity, however, was attenuated by both pregnancy and lactation. A further experiment compared the hypothermic effect of morphine in postpartum mice that were allowed to remain with pups and mice that were separated from pups. The enhanced hypothermia in the postpartum period was abolished by removing pups. This indicates that the altered response to morphine in the postpartum period was an effect of lactation rather than an aftereffect of pregnancy or parturition.

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The effect of morphine sulfate on the body temperature of the rat has been investigated. With a dose of 10 mg/kg administered intravenously there occurred a marked fall in core temperature and the degree and duration of hypothermia increased to give a maximum response with 35-50 mg/kg. Doses of 1 and 5 mg/kg caused either no change or a rise in temperature. Injection of 50 µg morphine sulfate into the region of the preoptic/anterior hypothalamic nuclei also led to a fall in core temperature, while injections into other regions of the hypothalamus were ineffective. Introduction of the drug into the area of the mammillary nuclei caused hyperactivity and hyperthermia. It is suggested that the hypothermic effect of morphine is due to depression of the set point of the thermoregulatory center in the anterior hypothalamus.

Luteinizing Hormone-Releasing Hormone Alters the Hypothalamic Effects of Morphine in the Rat*

Female rats exhibit a generalized refractoriness to opiate stimulation during periods of steroid-induced LH secretion. In the present study we evaluated that role of LHRH in this steroid-induced effect on opiate-responsiveness. Central administration to ovariectomized rats of native LHRH or the LHRH agonist [Des-Gly10]LHRH ethylamide causes a dose-dependent refractoriness to the hypothermic effects of morphine. The potency relationship of these two LHRH agonists in antagonizing morphine's effect was consistent with their potency in inducing LH release. Treatment of ovariectomized rats with estradiol benzoate and progesterone in a regimen which induces a preovulatory-like LH surge, antagonized morphine-induced hypothermia, and the LHRH antagonist [D-Phe2, Pro3, D-Phe6] LHRH, reversed the effects of the gonadal steroids. These results indicate that the LHRH secretory dynamics associated with the preovulatory surge of LH may serve to modulate opiate responsiveness and thereby could serve to couple behavioral, sensory, and autonomic events with this neuroendocrine response to gonadal steroids.

Cholecystokinin interferes with the thermoregulatory effect of exogenous and endogenous opioids

Intraperitoneal (ip) injection of cholecystokinin octapeptide sulfate ester (CCK; 5, 10 and 50 μg/kg) reduced the hypothermic response to 8 mg/kg and 32 mg/kg systemic morphine in restrained and freely moving rats, respectively. The hyperthermia elicited by a subcutaneous (sc) injection of 8 mg/kg morphine to freely moving rats was not diminished by CCK pretreatment. CCK (5 μg/kp ip) completely prevented the restraint stress-induced hyperthermia. Naloxone (1 mg/gk sc) was effective in antagonizing both the hyperthermic and the hypothermic effects of morphine and the stress-induced emotional hyperthermia. These results support the hypothesis that CCK may contribute to regulation of the endogenous opioid system.

Dissociation of tolerance to the analgesic and hypothermic effects of morphine by using thyrotropin releasing hormone

Dissociation of tolerance to the analgesic and hypothermic effects of morphine by using thyrotropin releasing hormone

Dissociation of tolerance to the analgesic and hypothermic effects of morphine by using thyrotropin releasing hormone

The effects of thyrotropin releasing hormone (TRH) on tolerance to the analgesic and hypothermic effects of morphine were determined in male Swiss Webster mice. The tolerance to morphine was induced by SC implantation of a morphine pellet containing 75 mg morphine free base for 3 days. Subcutaneous injections of TRH (4 mg/kg) twice a day inhibited tolerance to the analgesic effect of morphine, as evidenced by a greater degree of analgesia in TRH treated mice as compared with similarly treated vehicle injected controls. The same treatment, however, failed to modify tolerance to the hypothermic effect of morphine. These effects were produced with alterations in brain or plasma levels of morphine. It is concluded that tolerance to the two pharmacological effects of morphine may involve separate mechanism.

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.

Inability of cyclo (Leu-Gly) to facilitate the development of tolerance to and physical dependence on morphine in the rat

The effect of cyclo (Leu-Gly), an analog of melanotropin release inhibition factor on the development of tolerance to and physical dependence on morphine in the rat was investigated. Administration of cyclo (Leu-Gly) (1 μg/rat/day) prior to and during morphine pellet implantation failed to facilitate the development of tolerance to the analgesic and hypothermic effects of morphine. Similarly the development of dependence on morphine was not facilitated by cyclo (Leu-Gly) as evidenced by changes in body weight and body temperature observed during abrupt withdrawal of morphine. These studies do not lend support to the previous observations that cyclo (Leu-Gly) and other related peptides facilitate the development of tolerance to and physical dependence on morphine.

The effect of morphine pretreatment on hypothermia induced by morphine in mice

Morphine caused an apparently dose-dependent hypothermia in mice. Co-administration of naloxone antagonised this effect. Pretreatment with a single dose of morphine induced detectable tolerance to the hypothermic effect of a second dose of morphine given 3 h later and naloxone was more effective in antagonising the hypothermic effect of morphine in morphine-pretreated mice than in saline-pretreated animals. The present study has shown that morphine pretreatment can augment the antagonistic effect of naloxone towards the hypothermic action of morphine.

Effect of muscarinic cholinergic drugs on morphine-induced catalepsy, antinociception and changes in brain dopamine metabolism

The effects of drugs acting on muscarinic cholinergic receptors on the catalepsy, antinociception and changes in rectal temperature and in brain dopamine metabolism induced by morphine were studied in Wistar rats. Scopolamine (0.3 - 30 mg/kg) was about three times as potent as atropine (1 - 30 mg/kg) in potentiating the cataleptic effect of morphine. Methylscopolamine and methylatropine did not alter the cataleptic effect of morphine. Pilocarpine (100 mg/kg) and arecoline (10 mg/kg) slightly but significantly and RS86 (20 - 40 mg/kg) clearly antagonized the morphine-catalepsy. RS86 antagonized the atropine-induced potentiation of morphine catalepsy. The antinociceptive effect of pilocarpine was additive and that of RS86 less than additive with morphine. The antimuscarinic compounds did not alter the antinociceptive effect of morphine. Antimuscarinic compounds enhanced the hypothermic effect of morphine, but none of the compounds studied altered the hyperthermic effect of morphine. The antimuscarinic drugs reduced the concentration of striatal homovanillic acid (HVA) in about same proportion in control and morphine-treated rats. Both the muscarinic compounds and morphine increased the concentration of striatal HVA, but when combined their effects were not significantly different from those of morphine alone. Scopolamine antagonized and pilocarpine accelerated the morphine-induced increase in the rate of depletion of cerebral dopamine content. The present results show that the effects of muscarinic aand antimuscarinic cholinergic drugs on the cataleptic effect of morphine were opposite to their effects on the catalepsy induced by neuroleptic compounds.

Effect of acute and chronic morphine treatment on serotonin uptake into rat hypothalamic synaptosomes.

The effect of morphine on uptake of serotonin into hypothalamic synaptosomes was determined following acute and chronic morphine treatment in the rat. The uptake of serotonin was noncompetitively inhibited by in vitro morphine (IC50 = 7 X 10(-4) M) but not by an acute morphine treatment (30 mg/kg s.c.) which produces hypothermia. Uptake of serotonin into hypothalamic synaptosomes derived from rats rendered tolerant to the hypothermic effect of morphine or rats withdrawn from morphine was not altered either in the absence or presence of in vitro morphine as compared to control rats. These data indicate that alterations in thermoregulatory responses of the rat to either acute or chronic morphine treatment do not result from morphine-induced modification of serotonin uptake into hypothalamic neurons.

The effect of N-allylnormorphine on the development of acute tolerance to the analgesic and hypothermic effects of morphine in the rat.

The effect of N-allylnormorphine on the development of acute tolerance to the analgesic and hypothermic effects of morphine in the rat.

Heat production and heat loss in the rat following intracerebral and systemic administration of morphine

The fall in core temperature of the rat following either intravenous administration of morphine sulfate or injection of the drug into the anterior hypothalamus is accompanied by a pronounced reduction in oxygen consumption. No significant change in skin blood flow occurred after morphine. The mean rate of fall in temperature in the group of animals injected systematically was greater than that of the animals receiving intracerebral injections. This difference is regarded as an action of morphine apart from the effect of the drug on the thermoregulatory centers. It is concluded that the hypothermic effect of morphine is due to a reduction in metabolic heat production rather than to an increase in heat loss.