Involvement of NMDA receptors and nitric oxide in the thermoregulatory effect of morphine in mice (original) (raw)
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Journal of Neurochemistry, 2008
Previous evidence demonstrates that low dose morphine systemic administration induces acute thermal hyperalgesia in normal mice through lOR stimulation of the inositol signaling pathway. We investigated the site of action of morphine and the mechanism of action of lOR activation by morphine to NMDA receptor as it relates to acute thermal hyperalgesia. Our experiments show that acute thermal hyperalgesia is blocked in periaqueductal gray with the lOR antagonist CTOP, the NMDA antagonist MK801 and the protein kinase C inhibitor chelerythrine. Therefore, a site of action of systemically administered morphine low dose on acute thermal hyperalgesic response appears to be located at the periaqu-eductal gray. At this supraspinal site, lOR stimulation by systemically morphine low dose administration leads to an increased phosphorylation of specific subunit of NMDA receptor. Our experiments show that the phosphorylation of subunit 1 of NMDA receptor parallels the acute thermal hyperalgesia suggesting a role for this subunit in morphineinduced hyperalgesia. Protein kinase C appears to be the key element that links lOR activation by morphine administration to mice with the recruitment of the NMDA/glutamatergic system involved in the thermal hyperalgesic response.
Effect of periaqueductal morphine injection on thermal response in rats
The Japanese Journal of Physiology, 1986
The effect of morphine injection into the midbrain periaqueductal gray (PAG) was examined on thermal response in rats. Rectal temperature (Tre) was recorded in unanesthetized and unrestrained animals before and after PAG morphine injection of 5 or l0,tg in cold (10°C), neutral (22°C), and hot (34°C) environments. Both doses of morphine cuased hyperthermia. Sixty to 105 min after the injection, Tre rose by 1.0-1.5°C regardless of ambient temperature. Naloxone (2 mg/kg, i.p.) blocked the hyperthermic effects of morphine. Injection sites producing hyperthermia were distributed mostly in the ventral PAG and its ventral environs. The analgesic effect of morphine was examined by the tail-flick test. Locations of morphine injection effective for producing analgesia were restricted to the ventral area of the region responsible for hyperthermia. Magnitude of the hyperthermia did not significantly differ between animals with or without analgesia. The effect of PAG morphine (5 µg) was tested on tail vasomotor response to hypothalamic and scrotal thermal stimulations in urethane anesthetized (1.0 g/kg) animals. Threshold hypothalamic temperature for the vasodilation was lower at a scrotal temperature of 40°C than at 30°C. Following PAG morphine, threshold hypothalamic temperature rose and the difference in threshold hypothalamic temperature at the two scrotal temperatures disappeared. Key words ; morphine, midbrain periaqueductal gray, rectal temperature, vasomotor activity, rat. Morphine has repeatedly been reported to affect body temperature (for references see CLARK and CLARK, 1980). The effect varies with dose and with route of administration. When injected into the midbrain periaqueductal gray (PAG) of rats placed in a thermoneutral environment, both morphine and /3-endorphin elicit dose-dependent increases in rectal temperature (TSENG et al., 1980; WIDDowsoN et
Differential effects of morphine on core temperature in stressed and non-stressed rats
European Journal of Pharmacology, 1985
The effects of morphine on body temperature were studied in rats in two different states-stressed and non-stressed. Morphine injected subcutaneously (s.c.) produced a dual action on body temperature in non-stressed rats. Hyperthermia occurred at lower doses (2.5-10 mg/kg) while hypothermia was produced with a higher dose (20 mg/kg). Both of these effects of morphine were reversed by naloxone (0.1-5.0 mg/kg). Stressing the rats (immobilization with wire mesh) produced slight hypothermia which was markedly potentiated by morphine (5-20 mg/kg) in a dose-dependent manner. Enhancement of hypothermia by morphine in the stressed animals was antagonized by pretreatment with naloxone (0.1-5.0 mg/kg). When rats were treated with morphine (10 mg/kg) 1 h before stress, and were then exposed to immobilization stress, the hyperthermia exhibited in the non-stressed state changed to hypothermia in the stressed state. When the rats which were treated with morphine and then stressed for 1 h were released from stress, the hypothermia observed in the stressed state progressively changed to hyperthermia. Furthermore, these morphine effects, i.e. hyper-and hypothermia in the non-stressed and stressed states, respectively, were reversed but not eliminated by naloxone. These results suggest that the effects of morphine on core temperature in rats are altered depending upon the state of the animals. That is, morphine appears to have a dual action, hyperthermia in the non-stressed state and hypothermia in the stressed state. It also appears that these actions are mediated via opiate receptors.
Interaction between the effects of stress and morphine on body temperature in rats
Life Sciences, 1981
The relation between stress-induced and morphine-induced body temperature changes was examined in rats. Three groups of eight animals thoroughly habituated to handling and rectal probing, and three groups of eight experimentally naive animals were injected intraperitoneally with either i, 5, or 30 mg/kg morphine sulphate on each of six consecutive days. Differences in temperature readings from the pre-injection baseline showed that on Day 1 of the experiment stress acted to effectively increase the potency of morphine, causing slightly increased hyperthermia at the lowest dose and greatly increased hypothermia at the highest dose. Thus for habituated animals the dose-response curve for morphine was shifted to the right. By Day 6, after repeated morphine injections, all animals showed a hyperthermic response to morphine and the differences between habituated and unhabituated animals had disappeared. These findings were discussed in terms of the interaction between the temperature changes produced by endogenous opioids in stressed animals and the actions of exogenously administered morphine. Recent studies have pointed to a major role for endogenous opioids in thermoregulation. In rats, initial handling and rectal probing results in a rise in body temperature, presumably stress-induced, that can be prevented by the prior administration of naloxone (i, 2). Furthermore, Blasig et al. (i) have shown that only the active enantiomer (-)-naloxone blocked the hyperthermia; (+)-naloxone was ineffective. Stewart and Eikelboom (2) found that in unstressed animals, or in hypophysectomized animals, naloxone induces a dose-related decrease in body temperature relative to a saline control group. These findings combined with the fact that centrally administered endogenous opioids produce temperature changes similar to the biphasic changes found after morphine administration (3, 4, 5) have led us to explore the possible interaction between the temperature changes produced by endogenous opioids in stressed animals and the actions of exogenously administered morphine.
Endogenous morphine modulates acute thermonociception in mice
Journal of Neurochemistry, 2002
The endogenous synthesis of morphine has been clearly demonstrated throughout the phylogenesis of the nervous system of mammals and lower animals. Endogenous morphine, serving as either a neurotransmitter or neurohormone, has been demonstrated in the nervous system of both vertebrates and invertebrates. As one of the effects of exogenous morphine is the modulation of pain perception, we investigated the effects that the depletion of endogenous morphine had on nociceptive transmission. The immunoneutralization of endogenous morphine from brain extracellular spaces was obtained through the intracerebroventricular administration of af®nity puri®ed anti-morphine IgG to mice, which then underwent the hot plate test. Endogenous morphine immunoneutralization decreased thermal response latency and attenuated the anti-nociceptive effect of the mu selective agonist DAMGO in hot plate test suggesting that endogenous morphine is involved in pain modulation.
Morphine and d-Amphetamine Nullify Each Others' Hypothermic Effects in Mice
Pharmacology and Toxicology, 2003
We have examined the effects of the psychostimulant d-amphetamine and the neuroleptic haloperidol on hypothermia induced by intraperitoneal injection of the centrally penetrating opioids morphine, fentanyl and sufentanil and the peripherally acting opioid loperamide. Measuring rectal body temperatures, dose-response relationships were established for all compounds. Morphine and sufentanil produced hyperthermia at low doses and dose-related hypothermia at higher doses. Fentanyl and loperamide produced dose-related hypothermia. Fixed doses of each opioid producing significant hypothermia were selected for interaction studies. The psychostimulant d-amphetamine was found to produce biphasic effects with low doses inducing hypothermia and higher doses inducing hyperthemia. Haloperidol produced doserelated hypothermia. The selected doses of the opioids were then injected followed after 15 min. by injection of hypothermia producing doses of d-amphetamine or haloperidol. Hypothermia induced by morphine, fentanyl and sufentanil was reversed by d-amphetamine whereas loperamide-induced hypothermia was unaffected. Rebound hyperthermia was also measured with fentanyl and sufentanil. Haloperidol increased the hypothermic effects of morphine, fentanyl and sufentanil but not of loperamide. In conclusion, the central stimulating effects of opioids and amphetamine may combine resulting in thermogenesis and reversal of hypothermia. Central mechanisms of opioid-induced hypothermia in mice are influenced by drugs which alter the dopamine system, whereas peripheral mechanisms are unaffected. A possible clinical implication for this dopaminergic interaction may be toxicity associated with hyperpyrexia caused by psychostimulant misuse, which is increasingly occurring concomitantly with abuse of opioids.