Involvement Of Opioid Peptides Research Articles

Role of opioid peptides in the regulation of DNA synthesis in immature rat uterus

The effects of a single dose of naloxone and of [D-Met2, Pro5]enkephalinamide on the DNA synthesis in the uterus of 7, 14 and 21-day-old rat were studied. After [D-Met2,Pro5]enkephalinamide treatment, an age-dependent decrease in in vitro [3H]thymidine incorporation into DNA was observed in all studied age groups. In the 21-day-old age group a reduced rate of DNA synthesis was detected for 12 h after [D-Met2,Pro5]enkephalinamide treatment followed by the return to control values at 24 h. The rate of inhibition was more marked in the younger age groups. The effect of [D--Met2,Pro5]enkephalinamide treatment was completely prevented by the opioid antagonist naloxone injected 30 min prior to the agonist treatment. Naloxone itself resulted in an increase in uterine DNA synthesis. This effect was also more pronounced in younger animals. Specific [3H]naloxone binding was detected both in membrane and nuclear fractions of uterine homogenates. While no age-related changes in binding affinities were found, the number of binding sites varied characteristically during development. Our data suggest the novel involvement of opioid peptides and their receptors in the regulation of uterine development.

Evidence for the involvement of opioid peptides in phagocytosis, conformation, granulation and aggregation of immunocompetent Lumbricus terrestris amoebocytes

Opioid peptides and their analogs were shown to enhance Lumbricus terrestris amoebocyte phagocytosis, aggregation, granulation and conformation. These actions appear to be concentration dependent with 10 −8 M met-enkephalin and 10 −6 M dynorphin A having the greatest effect on the earthworm amoebocytes ( P < 0.05). Interleukin-1α significantly enhanced met-enkephalin mediated earthworm amoebocyte aggregation; leu-enkephalin mediated phagocytosis and aggregation; DAMA mediated phagocytosis; and U69,593 mediated phagocytosis, aggregation and conformation ( P < 0.05). Naloxone generally inhibited these activities indicating opioid receptor mediated mechanisms for earthworm amoebocyte function.

Opioid antagonist modulation of DNA synthesis in mouse tongue epithelium is circadian dependent

In addition to neuromodulation, endogenous opioids also serve as growth factors. To investigate the possible involvement of opioid peptides in the renewal of epithelium, mice were given systemic injections of the opioid antagonist, naltrexone (NTX) (10 mg/kg). Disruption of opioid-receptor interaction by NTX resulted in an elevation (43–150% from control levels) of the number of basal epithelial cells undergoing DNA synthesis in the tip, dorsal, and ventral surfaces of the tongue. This stimulatory effect lasted up to 8 h following drug exposure, and was recorded at 1700 h but not 0700 h. These results are the first indication that endogenous opioids function in cellular renewal processes, and do so in a circadian rhythm-dependent manner.

Involvement of Opioid Peptides from Casein on Reticular Motility and Digesta Passage in Steers

Experiment 1 determined the effects of incremental abomasal casein infusion on reticular motility and digesta passage of mature steers in a 4 × 4 Latin square study. Casein solutions were infused at 0, 1.25, 2.5, and 5.0% (wt/vol) for 3h at 16.7 ml/min. Steers were fed for maintenance every 2h. Casein resulted in a linear decrease in frequency, duration, and amplitude of reticular contractions measured manometrically. Total area of reticular contractions from physiographic tracings decreased 10.4 to 18.5%. Ruminal DM contents decreased 4.5 to 7.5%. Experiment 2 characterized the effects of casein on reticular contractions to be mediated by opioid peptides. Steers were infused abomasally (4h) with either a 5% (wt/vol) solution of casein or its hydrolysate with or without a predose of naltrexone as an opiate antagonist (.5mg/kg of BW) in a 2 × 2 factorial. Both casein and hydrolysate reduced frequency and duration of reticular contractions. Hydrolysate decreased contraction frequency within 30min of infusion and 60min prior to effects of casein. Naltrexone reversed the effects of casein and accentuated the effects of hydrolysate. Ruminal liquid outflow was decreased 19.7% with hydrolysate. Postruminal infusion of casein or its hydrolysate resulted in casomorphin-like activity on reticular motility and digesta passage.

Endogenous opioid mediation of the inhibitory effect of ethanol on the prolactin response to breast stimulation in normal women

The effect of ethanol on the prolactin (PRL) response to breast stimulation was tested in normal women. The possible role of endogenous opioids in the control of the PRL response to breast stimulation and ethanol action was also examined. Eleven normal women were tested four times on the 22nd day of four consecutive regular menstrual cycles. All women underwent mechanical breast stimulation (for 10 min) with the concomitant administration of normal saline, naloxone (2 mg in an iv bolus plus 10 mg over 75 min. or 4 mg in an iv bolus plus 20 mg over 75 min.), ethanol (50 ml in 110 ml of whiskey p.o.) or the combination of ethanol and naloxone. Serum PRL levels rose significantly after breast stimulation, with a mean peak response (71.4% higher than baseline at 20 min). The PRL response to breast stimulation was not changed by the treatment with the lower (2 plus 10 mg) or the higher (4 plus 20 mg) dose of naloxone, whereas it was strikingly decreased by ethanol (mean peak was 25% higher than baseline). However, when ethanol was given together with naloxone, the peak rise induced by breast stimulation was only partially inhibited by ethanol (the mean PRL peak was 46.2% higher than baseline). At both doses naloxone produced similar effects. These data demonstrate that ethanol inhibits the PRL response to breast stimulation. Naloxone-sensitive endogenous opioids do not appear to be involved in the control of the PRL rise induced by breast stimulation. In contrast, since naloxone partially reversed the inhibiting effects of ethanol, a partial involvement of opioid peptides in ethanol action is supposed.

Invertebrate and vertebrate neuroimmune and autoimmunoregulatory commonalties involving opioid peptides.

1. Evidence for bidirectional interrelationships between the nervous system and immune systems of vertebrates and invertebrates involving opioid peptides is briefly discussed. 2. The involvement of opioid peptides in autoimmunoregulatory communication also is discussed. 3. The presence of mammalian interleukin-like (1 & 6) and tumor necrosis factor-like molecules in invertebrates is reviewed as well as an apparent cascading system for these signal molecules. 4. The significance of ACTH and MSH in cellular immunosuppression and autoimmunoregulation is discussed in the context of a potential role in schistosomiasis and human immunodeficiency virus actions. 5. The review concludes with the hypothesis that the mammalian immune system has its origin in the invertebrate immune/defense system given the many similarities noted in the review based on new knowledge about the more "primitive" system.

Inhibition by ethanol of the oxytocin response to breast stimulation in normal women and the role of endogenous opioids.

The possible inhibition exerted by ethanol on the oxytocin response to breast stimulation was tested in normal women. The possible role of endogenous opioids in the control of the oxytocin response to breast stimulation and/or ethanol action was also examined. Sixteen normal women were tested four times on the 22nd day of four consecutive regular menstrual cycles. All women underwent mechanical breast stimulation (for 10 min) with the concomitant administration of normal saline, naloxone (2 or 4 mg in an iv bolus plus 5 or 10 mg over 16 min), ethanol (50 ml in 110 ml of whisky po) or the combination of ethanol and naloxone. Plasma oxytocin levels rose about twofold after breast stimulation, with a mean peak response at 10 min. The oxytocin response to breast stimulation was not changed by the treatment with the lower (2 plus 5 mg) or the higher (4 plus 10 mg) dose of naloxone, whereas it was completely abolished by ethanol. However, when ethanol was given together with naloxone, the oxytocin rise induced by breast stimulation was only partially inhibited by ethanol (the mean oxytocin peak was 50% higher than baseline). At both doses naloxone produced similar effects. These data demonstrate that ethanol inhibits the oxytocin response to breast stimulation. Naloxone sensitive endogenous opioids do not appear to be involved in the control of the oxytocin rise induced by breast stimulation. In contrast, since naloxone partially reversed the inhibiting effects of ethanol, a partial involvement of opioid peptides in ethanol action is supposed.

Some mechanisms of involvement of opioid peptides in the regulation of carbohydrate metabolism

Some mechanisms of involvement of opioid peptides in the regulation of carbohydrate metabolism

Possible participation of endogenous opioid peptides on the mechanism involved in analgesia induced by vouacapan

The involvement of opioid peptides in the mechanism of action of vouacapan, a new experimental compound extracted from seeds of Pterodon poligalaeflorus Benth, was investigated both in mice utilizing acetic acid writhing response and in rats utilizing inflammatory hyperalgesia induced by carrageenan and modified Randall-Selitto method. Vouacapan, in both models, caused a dose-dependent analgesia when injected p.o., s.c. and i.p. The analgesic effect was partially blocked by naloxone, nalorphine and n-methyl-nalorphine. Significant tolerance to analgesic effect was observed following repeated administration of vouacapan or morphine. On the last day of treatment, cross administration revealed symmetrical and asymmetrical cross-tolerance between vouacapan and morphine, in rats and mice, respectively. We conclude that a release of endorphins could be involved in the analgesic mechanism of vouacapan in both models studied.

Facilitation of dimethylbenz[a]anthracene-induced rat mammary tumorigenesis by restraint stress: role of β-endorphin, prolactin and naltrexone

In order to investigate the involvement of opioid peptides and prolactin in stress-facilitated mammary cancer, we studied the effect of chronic restraint stress on dimethylbenz[a]-anthracene (DMBA)-induced mammary tumorigenesis and the effect of an opiate antagonist, naltrexone, on this process. Female Fischer-344 rats (n = 160) were administered 15 mg DMBA/ml of sesame oil/rat by intragastric intubation. Eighty rats were subjected to daily 30 min restraint stress in a plastic cylinder, and 80 rats served as control not subjected to the stressor. Half of the rats from each group received naltrexone (1 mg/kg, i.p. daily). Five rats from each group (restraint stress +/- naltrexone and control +/- naltrexone) were killed every 2-3 weeks. Rats subjected to restraint stress developed a greater number of tumors earlier. Naltrexone decreased the tumor incidence in the stressed animals from 32 to 12% (P less than 0.001) and in unstressed rats from 27 to 15% (P less than 0.001) at the end of 18 weeks. Stressed rats showed a decrease of 48% (P less than 0.001) in the level of hypothalamic beta-endorphin. Plasma prolactin increased from 4-13 ng/ml in the control rats to 109-396 ng/ml (P less than 0.001) in the stressed rats throughout the 18 week period. The beneficial effect of naltrexone was associated with 42% (P less than 0.01) increase in T cell proliferation, but greater than 90% (P less than 0.001) decrease in plasma prolactin level was observed in naltrexone-treated rats compared to the untreated animals. Rats subjected to restraint stress showed a 15% (P less than 0.001) decrease in weight gain at the end of the experiment (18 weeks). Neither restraint stress nor naltrexone administration affected the caloric intake of rats during this period. Thus, we believe that restraint stress facilitates DMBA-induced mammary tumors by releasing beta-endorphin and prolactin, and naltrexone shows a beneficial effect by opposing the effect of beta-endorphin on prolactin release in the stressed animals.

Periovulatory Plasma Prolactin Response to Gonadotropin-Releasing Hormone: Role of Endogenous Opiates

It has been previously shown that in normal women during the periovulatory period, prolactin (PRL) levels increase after the administration of nonspecific stimuli, such as growth hormone-releasing hormone or gonadotropin-releasing hormone (GnRH). In order to gain insight into the mechanism of this response, we have tested the effect of a naloxone infusion (1.6 mg/h) on the PRL response to GnRH in 5 normal females, aged 20-27 years, tested during the periovulatory period. Naloxone was administered starting 60 min before GnRH administration (100 micrograms as an i.v. bolus). Naloxone clearly blunted the PRL response (basal 10.7 +/- 1.7 ng/ml, peak 11.8 +/- 0.2 ng/ml at 30 min, versus: basal 9.0 +/- 0.5 ng/ml, peak 20.6 +/- 3.9 ng/ml at 45 min after GnRH alone; significance of difference between peaks: p less than 0.05). A secondary late increase of PRL levels was observed, reaching about 60% of basal levels at 120 min (16.8 +/- 2.6 ng/ml). These data indicate that periovulatory PRL dynamics are altered by naloxone administration and suggest a possible involvement of opioid peptides in the 'paradoxical' PRL response to GnRH in normal subjects.

Inhibitory Effect of Ethanol on the Arginine Vasopressin Response to Insulin-Induced Hypoglycemia and the Role of Endogenous Opioids

The present study was undertaken in order to establish whether ethanol is able to modify the arginine vasopressin (AVP) response to insulin-induced hypoglycemia in man. In addition, the possible involvement of opioid peptides in the mediation of hypoglycemia and/or ethanol action was investigated. For these purposes, the AVP response to an intravenous (0.15 U/kg) insulin tolerance test (ITT) was measured in 6 normal men treated with saline, naloxone (2 or 4 mg as intravenous bolus plus 5 or 10 mg infused over 105 min), ethanol (50/110 ml of whiskey p.o.), or the combination of ethanol and naloxone. Plasma AVP levels rose by about three-fold during insulin-induced hypoglycemia; administration of naloxone did not modify, whereas ethanol completely abolished the AVP response during ITT. When ethanol was given together with naloxone, AVP rose by only two-fold in response to hypoglycemia. Neither ethanol nor naloxone modified the basal secretion of AVP as tested during 45 min before the ITT. These data demonstrate that ethanol inhibits the AVP response to hypoglycemia. Naloxone-sensitive endogenous opioids do not seem to be involved in the control of basal and hypoglycemia-induced AVP secretion. In contrast, since naloxone partially reversed the inhibiting effects of ethanol, a partial involvement of opioid peptides in ethanol action may be supposed.

Naloxone abolishes the inhibiting effect of somatostatin on the release of oxytocin evoked by insulin-induced hypoglycemia in humans

The effect of somatostatin (SRIH) on the release of oxytocin (OT) in response to hypoglycemia during insulin tolerance test (ITT) was studied in seven normal men. Subjects were injected intravenously with 0.15 U/kg insulin alone (control test) or together with SRIH (4.1 μg/min × 90 min), naloxone (10 mg in an IV bolus), or the combination of the two substances. Plasma OT concentrations rose significantly during ITT; the OT response was significantly reduced by the treatment with SRIH and increased in the presence of naloxone. When both SRIH and naloxone were given, the OT response to hypoglycemia did not differ from that observed in the control test. These findings provide evidence that the effect of hypoglycemia on plasma OT levels is sensitive to the inhibition by SRIH and by naloxone-sensitive endogenous opioids. Because naloxone reversed the inhibiting effects of SRIH, an involvement of opioid peptides in SRIH action might be supposed. Alternatively, SRIH and naloxone-sensitive opioids might produce their inhibiting effects on OT rise in response to hypoglycemia through independent pathways.

Habituation and dehabituation of the spinal polysynaptic reflex responses: Modification by naloxone and opiates and their anatomical correlates

The sustained inhibitory action of spinal endorphins could be responsible for the habituation of polysynaptic responses in the spinal cord. To test this hypothesis, acute spinalized unanesthetized cats (decerebrated and curarized) were used. Sural nerve electrical stimulation (0.2 Hz) was provided and a progressive decrease in the reflex response was found. Conversely, the field potential (lamina V) progressively increased during stimulation, reaching its maximum amplitude when ventral root response showed maximum habituation. The administration of naloxone (0.8–10.0 mg/kg) produced dehabituation or prevented habituation. The immunohistological results showed leu-enkephalin-like immunoreactive dot-like structures in close proximity to neurons of laminae VII, VIII and IX in the lumbo-sacral segment of the spinal cord. Our results suggest an involvement of opioid peptides in the habituation process.

The involvement of opioid peptides in stress-induced analgesia in the slug Arion ater

Application of tail-pinch stress to the terrestrial slug, Arion ater, produced a significant increase in the response time when tested on the hot-plate for foot-lifting response. The analgesia was completely reversed by injections of the opiate antagonists, naltrexone and ICI 174864, in a dose-dependent manner. Analgesia could also be elicited by the injection into the foot of beta-endorphin and the enkephalin analogues, DAGO and DADLE. No effect was seen with dynorphin A (1-8) or dynorphin A (1-17). The stress-induced analgesia disappeared after 30 minutes but could be maintained for 100 min following the injection of a mixture of bestatin and the enkephalinase inhibitor, N-carboxymethyl-L-phenylalanyl-L-leucine. This work suggests that in the slug, a physical stressor produces an analgesia which may be due to the release of endogenous opiates.

Antidepressant action of imipramine and iprindole in mice is enhanced by inhibitors of enkephalin-degrading peptidases

The implication that opioid peptides are involved in the action of the antidepressants imipramine and iprindole was investigated in mice by using the forced swimming test as an experimental model of depression. Both the drugs were found to shorten the immobility time in this test. This effect of impramine and iprindole was reversed by the opiate antagonist naloxone. Moreover, when subeffective doses of either imipramine or iprindole were given together with an intracerebroventricular injection of an inhibitor of their degradation (thiorphan or bestatin), the immobility time was again decreased. Interestingly, the reduction of the time of immobility was found to be not related to the effect of the drugs on locomotor activity. These data might be taken as further evidence for the involvement of opioid peptides in the pharmacological action of antidepressant drugs.

Naloxone decreases the inhibiting effect of ethanol on the release of arginine-vasopressin induced by cigarette smoking in man

In order to establish whether ethanol exerts its inhibiting effect on the nicotine-induced release of arginine-vasopressin (AVP) by interacting with an opioid pathway, six normal volunteers were treated with naloxone (2 or 4 mg as IV bolus, plus 5 or 10 mg infused over 105 minutes) during (2 nonfilter) cigarette smoking and ethanol (50 mL to 110 mL of whiskey) drinking. In addition, control experiments with naloxone, ethanol, or cigarette smoking alone were performed. When given alone, naloxone and ethanol did not modify AVP secretion, whereas nicotine increased plasma AVP levels by about 2.5-fold. This effect was completely blocked by ethanol. In the presence of naloxone, AVP rose only by about 1.7-fold in response to nicotine. Since naloxone only partially reversed the inhibiting effects of ethanol, only a partial involvement of opioid peptides in ethanol action might be supposed. Alternatively, ethanol and naloxone-sensitive opioids might produce their inhibiting effects on AVP rise in response to nicotine through independent pathways.

Antagonism of the stimulant and depressant effects of ethanol in rats by naloxone.

The action of naloxone (0.5 and 2 mg/kg IP) on the behavioural effects of a low (2 g/kg PO) and a high dose (4 g/kg PO) of ethanol was studied in rats. Ethanol at the low dose increased spontaneous motility, enhancing open-field external ambulations and reducing shuttle-box latency. All these effects were antagonized by naloxone. Ethanol at the high dose produced by hypomotility, decreasing open-field external ambulations and impairing shuttle-box performance. In this case, naloxone also reduced the ethanol effect, but its action was less consistent. Therefore, although mechanisms other than a specific opioid receptor blockade by naloxone must be considered, an involvement of opioid peptides in the effects of ethanol cannot be discounted.

Naloxone and beta-endorphin alter the effects of post-training epinephrine on memory.

These experiments examined the involvement of opioid peptides in the memory-modulating effects of post-training epinephrine (Epi). Mice were trained on inhibitory avoidance (IA) and Y-maze discrimination (YMD) tasks and given post-training injections followed by retention tests 24 h later. In the IA task retention was enhanced by low doses of Epi and impaired by high doses. In both tasks, naloxone facilitated retention and blocked the memory-impairing effects of Epi. These findings are consistent with other evidence suggesting that the memory-impairing effects of beta-endorphin are mediated by the release of opioid peptides. Previous studies have shown that a novel exploratory experience given 1 h prior to training blocks the release of brain beta-endorphin and blocks the memory-enhancing effects of post-training naloxone. In the present study we found that a novel experience given 1 h prior to training blocked the memory-impairing effect of post-training Epi otherwise obtained in both tasks. The effects of a low, memory-enhancing dose of Epi appear not to involve the release of opioid peptides: a low dose of Epi blocked the memory-impairing effect of beta-endorphin. Further, low doses of Epi and naloxone, which were ineffective when administered alone, significantly enhanced retention when administered together. We interpret these findings as indicating that the memory-enhancing and memory-impairing effects of Epi are mediated by different mechanisms.

Evidence for an involvement of opioid peptides in exercise-induced lipolysis in rats.

Evidence for an involvement of opioid peptides in exercise-induced lipolysis in rats.