Effect Of Morphine Pretreatment Research Articles

Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus.

Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling. A time-dependent effect of morphine (1 mg·kg(-1) , i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c-Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light-induced pERK and c-Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [(35) S]-GTPγS binding assay. Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light-induced level of pERK1/2 and c-Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN. Our data suggest that the phase-shifting effect of opioids may be mediated via post-translational modification of clock proteins by means of activated ERK1/2 and GSK3β.

The effect of morphine pretreatment on the sensitivity of mouse and guinea-pig ileum to acetylcholine and to morphine.

Abstract Guinea-pigs and mice were subjected to morphine pretreatment for at least 14 days culminating in subcutaneous injections of 1 g/kg daily in 2 divided doses. In mice, tolerance to the effects of morphine on gastrointestinal propulsion had developed by the end of the pretreatment course. The sensitivity to acetylcholine of the ilia from pretreated animals and the effects of morphine on transmural stimulation were compared with the ilia from normal animals. Ilia from pretreated guinea-pigs were marginally more sensitive to frequency of stimulation but significantly less sensitive to the depressant effect of morphine than ilia from normal animals. There was no significant difference in the sensitivity to acetylcholine. There was a highly significant decrease in sensitivity to morphine of ilia from pretreated mice, but this also was not associated with any alteration in sensitivity to acetylcholine. It is concluded that on the isolated ileum preparation the development of tolerance to morphine is not associated with an increased sensitivity to the transmitter whose release morphine inhibits.

Blood luteinizing hormone and prolactin concentrations in response to naltrexone challenge: Studies on rats with diabetes induced by different doses of streptozotocin

Opiate system involvement in diabetes induced by three different doses of streptozotocin (STZ; 40, 50, and 60 mg/kg body weight [BW]) was studied by monitoring luteinizing hormone (LH) and prolactin (PRL) levels as a response to naltrexone (Nalt) administration. After four weeks of diabetes a marked decrease in BW, as well as severe hyperglycemia and increased blood urea nitrogen (BUN) levels were found. The rats, whose diabetes was induced by 50 mg/kg of STZ, exhibited the highest amount of blood glucose ( P < 0.05, compared with the 40 mg/kg induced group) and BUN levels ( P < 0.004 compared with the order two groups) and BW loss. The normal response to Nalt, which is expressed by elevation of plasma LH and decreased plasma PRL levels was observed only in the low-dose STZ (40 mg/kg BW) diabetes-induced group, while in the other two diabetic groups (50 and 60 mg/kg BW) there was no significant change in plasma LH and PRL as a result of the Nalt challenge. Presensitization of the endogenous opioid receptors by morphine in normoglycemic (control) and “low-dose diabetic” rats (40 mg/kg BW of STZ), presented a clear difference between the two. Morphine pretreatment inhibited LH response to Nalt in the low-dose, STZ-induced diabetic rats, while no effect of morphine pretreatment on LH response to Nalt could be recorded in the normoglycemic group. Thus it can be concluded that in STZ-induced diabetes, plasma glucose and BUN levels do not reflect the neuroendocrine injury observed when monitored by LH and PRL secretion in response to Nalt challenge. Supersensitization of the opioid receptors before the Nalt challenge may increase the ability to reveal neuroendocrine system impairment.

Histamine-caused itch induces Fos-like immunoreactivity in dorsal horn neurons: effect of morphine pretreatment

It is well known that cutaneous pain causes c- fos gene expression in the dorsal horn neurons. The present study examined whether or not an itching sensation had the same effect on these neurons. In order to produce an itching sensation, cotton balls soaked in histamine solutions of different concentrations were applied to the lower limbs of rats and then the treated area was scratched with the tip of a pair of forceps. After 2 h, the number of neurons showing Fos-like immunoreactivity was significantly increased in a dose-dependent manner in the ipsilateral dorsal horn when compared to saline-treated and scratched controls. When scratching with the forceps was omitted, the number of these neurons was reduced to one-third, but was still significantly higher than in controls treated only with saline. Expression of Fos-like immunoreactivity in these animals was markedly reduced by morphine pretreatment (10 mg/kg, i.p.), suggesting that the transmission of both itch and pain is blocked by morphine.

Morphine inhibits TRH-induced gastric contractile activity

This study investigated the effect of centrally and peripherally administered thyrotropin releasing hormone (TRH) on gastric contractile activity of rats 14, 21, 28 and adult (≥50) days (D) of age, and the effect of morphine pretreatment on that response. Rats were anesthetized with urethane, then a tension transducer was implanted on the anterior gastric corpus. Following baseline recording, rats were pretreated with intraperitoneal morphine (2 mg/kg). TRH (5 μg) in saline or saline alone (0.6 μl) was then injected into the cisternum magnum. Additionally, dose response to TRH was examined in 14- and 50-day-old rats. Intracisternal TRH induced a dose-related increase in gastric contractile activity in both 14- and 50-day-old rats. Higher doses of TRH (10 and 30 μg) prolonged the response as compared to low doses. Peripheral morphine pretreatment blocked the TRH-induced increase in gastric contractile activity in all age groups although a higher morphine dose (10 mg/kg) was needed to block the effect in 28D rats. Intravenous TRH (5, 10, 30 μg) produced an increase in gastric contractile activity in 14D rats which was blocked by vagotomy.

Potentiating effect of morphine on seizures induced by kainic acid in rats. An electroencephalographic study.

The effect of morphine pretreatment on kainic acid-induced seizures in rats was investigated by electroencephalographic recording. Seizure activity was quantified by counting the number of spikes in the EEG of freely-moving rats during 2 min periods at 30 min intervals after the intraperitoneal administration of 8, 10 or 12 mg/kg kainic acid. Pretreatment with morphine (1-10 mg/kg s.c.) 10 min before kainic acid administration significantly increased the number of spikes in the EEG in a dose-dependent manner. The potentiating effect of morphine on kainic acid-induced seizures was reduced considerably, but not abolished completely by pretreatment with naloxone (2-5 mg/kg s.c.). The results indicate that the potentiating action of morphine on kainic acid-induced seizures may be exerted in both a specific, naloxone-reversible manner and a non-specific, naloxone-resistant manner.

Effect of morphine pretreatment on pentylenetetrazol-induced seizures in the rat

In several species, larger doses of systemically-administered morphine induce seizures while smaller doses potentiate chemically-induced convulsions. However, it is generally considered that morphine acts as an anticonvulsant in the rat. In the present study, the effects of pretreatment with morphine on both electrical and motor manifestations of pentylenetetrazol (PTZ)-induced seizures in the rat were examined. Morphine (60 and 120 mg/kg) significantly delayed the onset of motor seizures induced by pentylenetetrazol but also induced a significantly greater number of motor seizures, a greater percentage of deaths and a lowering of the chemoconvulsive threshold for pentylenetetrazol. Recordings from animals with chronically-implanted supracortical electrodes showed that pretreatment with morphine (60 mg/kg) both altered the onset pattern of CNS excitation induced by pentylenetetrazol and delayed the onset of electrical seizure activity. These recorded electrocortical effects were similar to the behavioral effects observed in the non-implanted animals. Larger doses of morphine (175 and 250 mg/kg) by themselves produced both motor and electrocortical seizures in rats with chronically-implanted electrodes.

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.