Specific Opiate Receptors Research Articles

Effects of morphine on cold-induced TRH release from the median eminence of unanesthetized rats

The effect of morphine perfusion into the median eminence on cold-induced TRH secretion was studied in unanesthetized rats by push-pull cannulation. Perfusion with 10 −6M morphine blocked the cold-induced TRH peak occuring about 40 min after the transfer of rats from 24°C to 4°C. This inhibition by morphine was blunted by concomitant administration of naloxone (10 −6M or 10 −5M), but naloxone alone had no effect on either basal or cold-induced TRH release. We conclude that specific opiate receptors may be located on TRH nerve endings in the ME, and than endogenous opiates may not have any physiological role in the cold-induced TRH response, at least during the two hours that follow cold exposure.

Inhibitory effect of beta-endorphin on gonadotropin-releasing hormone and thyrotropin-releasing hormone releasing activity in cultured rat anterior pituitary cells.

To study the effect of human beta-endorphin (beta h-End) on pituitary response to gonadotropin-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) in vitro, we used dispersed rat pituitary cells. When beta h-End (10(-7) M) was simultaneously added along with LH-RH, its stimulatory effect was blocked and naloxone (NAL, 10(-5) M) did not reverse the beta h-End inhibitory effect. NAL alone elicited an increase in LH release, but in the presence of both stimulants (LH-RH and NAL), LH secretion was lower than that observed with LH-RH alone. TRH stimulatory activity of TSH and PRL secretion was blunted by the presence of beta h-End (10(-7) M) and was not reversed by NAL (10(-5) and 10(-3) M). These data suggest that beta h-End directly blocks the LH, TSH- and PRL-secreting activity of both LH-RH and TRH at the pituitary level. This beta h-End effect is not reversed by the specific opiate receptor blocker NAL.

Effect of insulin on secretion of bombesin-like immunoreactivity and gastrin from the isolated rat stomach in response to acetylcholine, VIP and leucine-enkephalin

Bombesin-like immunoreactivity (BLI), a putative peptidergic neurotransmitter of the gastrointestinal intrinsic nervous system is released from the isolated perfused rat stomach in response to the classical neurotransmitter acetylcholine and in response to other putative peptidergic neurotransmitters such as vasoactive intestinal peptide (VIP), peptide histidine isoleucine (PHI) or growth hormone releasing factor (GRF). The secretion of BLI is modulated not only by gastric factors such as the intragastric pH but also by changes of perfusate glucose concentrations indicating that alterations of carbohydrate metabolism might have an effect on gastric neuroendocrine regulation. Since previous studies have shown that insulin, the major regulatory hormone of glucose metabolism, reduces gastric somatostatin and glucagon secretion it was of interest to determine the effect of insulin on gastric BLI and gastrin secretion. The experiments were performed in the isolated perfused rat stomach model. The addition of porcine insulin to the perfusate at concentrations of 50 and 100 μU/ml had no effect on basal BLI and gastrin secretion. The infusion of acetylcholine (2 × 10 −6M and 4 × 10 −6M) elicited a stimulation of BLI and gastrin secretion which was not altered by the addition of insulin (100 μU/ml). On the other hand, significant effects of insulin were observed during administration of the two putative peptidergic neuro-transmitters VIP and leu-enkephalin. The infusion of VIP at 10 −11M and 10 −8M had no effect on BLI and gastrin secretion in the absence of insulin, however, with the addition of insulin (100 μU/ml) the higher dose of VIP (10 −8M) elicited a significant stimulation of BLI secretion while both doses of VIP (10 −11M and 10 −8M) significantly increased gastrin release. Simlar to VIP the infusion of leu-enkephalin at doses of 10 −9M and 10 −6M had no effect on BLI and gastrin secretion in the absence of insulin. When insulin was added to the perfusate both doses of leu-enkephalin elicited a significant stimulation of BLI secretion while gastrin remained unchanged. The addition of the specific opiate receptor antagonist naloxone (10 −5M) did not block the effect of leu-enkephalin in the presence of insulin. In addition the effect of naloxone was also examined during cholinergic stimulation. The addition of naloxone (10 −5M) during the infusion of acetylcholine abolished the stimulatory effect on BLI secretion in the absence of insulin, whereas in the presence of insulin naloxone did not alter cholinergically-induced BLI secretion. In conclusion the present data demonstrate that in the rat stomach insulin has no effect on cholinergically-induced BLI and gastrin secretion but it augments BLI secretion in response to VIP and leu-enkephalin and gastrin release in response to VIP. This suggests that insulin has a modulatory effect on the action and release of putative peptidergic neurotransmitters of the rat peripheral autonomic nervous system. Furthermore, endogenous opioids apparently mediate the cholinergic stimulation of BLI secretion and insulin antagonizes the effect of the opiate-receptor antagonist naloxone via as yet unknown mechanisms.

Enkephalins have a direct positive inotropic effect on cultured cardiac myocytes.

Enkephalins have peripheral vascular effects, and enkephalinergic innervation of the heart has been reported. To determine whether enkephalins have direct effects on myocardium, we studied the effects of [D-Ala2, Met5]enkephalinamide and [D-Ala2, D-Leu5]enkephalin on amplitude of contraction (measured with an optical-video system) in spontaneously beating monolayer cultures of chicken embryo ventricular cells, a preparation devoid of intact neural elements. [D-Ala2, Met5]enkephalinamide and [D-Ala2, D-Leu5]enkephalin as well as [Met5]- and [Leu5]enkephalin increased contractility in a concentration-dependent manner. The enkephalin-induced maximal contractile effects were 28% and 30% above control, with EC50 values of 0.53 and 0.17 microM for [D-Ala2, Met5]enkephalinamide and [D-Ala2, D-Leu5]enkephalin, respectively. The positive inotropic effect was antagonized by naloxone but not by propranolol, phentolamine, diphenhydramine, or cimetidine. Naloxone alone had no effect on contractility at a concentration (0.1 microM) that blocked positive inotropic effects of [D-Ala2, Met5]enkephalinamide and [D-Ala2, D-Leu5]enkephalin. To demonstrate the presence of opiate receptors, we studied [3H]naloxone binding in homogenates of cultured chicken embryo ventricular cells. Analysis of binding curves under equilibrium conditions indicated that [3H]naloxone bound specifically to membranes of cultured heart cells with KD = 18.5 +/- 5.4 nM and Bmax = 46.8 +/- 11.7 fmol/mg of protein. We conclude that enkephalins exert a direct positive inotropic effect on cultured heart cells, increasing contractile state via specific opiate receptors.

Endogenous opioid peptides participate in the modulation of prolactin release in response to cervicovaginal stimulation in the female rat.

Naloxone, a specific opiate receptor antagonist, was used to evaluate the influence of endogenous opiate peptides on PRL secretion during various stages of the estrous cycle and after cervicovaginal stimulation. Naloxone (0.2 mg/kg, iv) administered at 0930 h suppressed basal 1000 h PRL levels on each day of the estrous cycle, but had no effect on the PRL surges occurring on the afternoon of proestrus and estrus. These afternoon surges could only be suppressed when naloxone was given immediately before the onset of the surge at 1330 h, suggesting a critical period for naloxone action. Later injections (at 1530 and 1730 h) had no further suppressive effects, although these injections suppressed the basal PRL secretion occurring during diestrous days I and II to near undetectable levels. In contrast, the immediate (1000 h) and afternoon PRL discharges triggered by cervicovaginal stimulation at 0930 h on proestrus, estrus, and diestrous day I were significantly suppressed by a single injection of naloxone, but only when it was administered before application of the stimulus. Moreover, this single naloxone injection significantly inhibited the long term PRL surges occurring during days 2 and 4 of pseudopregnancy in animals stimulated on estrus and diestrous day I. Naloxone treatment significantly shortened the duration of pseudopregnancy but did not prevent it, indicating that only minimal levels of PRL may be necessary to initiate and maintain pseudopregnancy. This striking difference in the time at which naloxone suppressed the stimulus-induced PRL discharges (compared to the spontaneous surges) suggests that endogenous opiate peptides also process the sensory information necessary for establishment of PRL surges during pseudopregnancy. The marked dependence of the spontaneous as well as the stimulus-induced PRL discharges on the stage of the estrous cycle support established evidence that ovarian steroids enhance endogenous opiate activity or facilitate the transfer of information along opiatergic pathways for the generation of PRL surges.

Counteraction by naltrexone of stress-induced inhibition of TSH release: role of noradrenergic system.

The purpose of the present study was to examine the effect of administering an opiate receptor antagonist, naltrexone (NALT) on the decline in pituitary thyrotropin (TSH) release induced by both acute and chronic stress, and to determine whether norepinephrine (NE) is involved in the mechanism by which opiate receptor blockade counteracts inhibition of TSH release during stress. Administration of NALT, a specific opiate receptor antagonist, significantly attenuated the decrease in plasma TSH observed after acute exposure to ether or restraint stress. The ability of NALT to prevent suppression of circulating TSH in ether-stressed rats was blocked by pharmacological suppression of NE activity induced by pretreatment with diethyldithiocarbamate (DDC) or phenoxybenzamine (PB), both NE antagonists. In chronically stressed rats, thrice daily injections of NALT attenuated the sustained decline in circulating TSH, and resulted in a significant elevation in plasma TSH when compared with stressed, saline-treated animals. Pretreatment with DDC prior to NALT injection abolished this stimulatory effect of NALT. These observations indicate that opiate/receptor interaction is prerequisite for the decrease in circulating TSH release during both acute and chronic stress, and support the hypothesis that endogenous opioid peptides (EOPs) mediate the suppressive effect of stress on TSH release. The finding that uninterrupted NE function is necessary for NALT's action on TSH release during stress suggests that the suppressive effect of stress on TSH and its reversal by opiate antagonists involves alterations in hypothalamic NE activity.

Effects of intravascular volume expansion on the cardiovascular response to naloxone in a canine model of severe endotoxin shock

The specific opiate receptor antagonist, naloxone, can produce haemodynamic improvement and increased survival in experimental shock. The efficacy of naloxone therapy in a canine model of endotoxin shock has been evaluated both with and without intravascular volume replacement. Animals were anaesthetized with alpha-chloralose and allowed to breathe spontaneously. A large bolus dose of endotoxin was followed by a continuous infusion and treatment was instituted one hour after the endotoxin bolus. In the absence of volume replacement, naloxone caused only limited and transient increases in mean arterial pressure (MAP) and left ventricular (LV) dp/dt max, with little effect on cardiac index (CI). Total peripheral resistance index (TPRI) tended to rise in both control and naloxone-treated dogs. In volume-replaced animals, naloxone produced substantial and sustained increases in the MAP and LV dp/dt max with an associated rise in the CI. TPRI rose initially in this series and then fell progressively. Further analysis of the improvements in the CI showed an increase in stroke index with a tendency for heart rate to fall. These findings suggest a myocardial action of naloxone in endotoxin shock, which is augmented by volume replacement. An initial, transient vasoconstrictor effect cannot, however, be excluded. Further work is required to determine the mechanism of the effects described.

Differential behavioral effects induced by intrathecal microinjection of opiates: Comparison of convulsive and cataleptic effects produced by morphine, methadone, and d-Ala 2-methionine-enkephalinamide

Intrathecal (i.t.) microinjection of 400 μg of morphine in rats induces convulsive activity restricted to the hindlimbs. This activity is potentiated rather than antagonized by naltrexone, is potentiated in animals pretreated over 6 days with increasingly higher systemic doses of morphine, and is potentiated and prolonged by high thoracic spinalization. Similar to morphine, convulsive spinal activity could also be elicited with i.t. injection of the non-opiate convulsant penthylenetetrazol (PTZ). However, methadone, d-ala 2-methionine-enkephalinamide (DALA), or naltrexone, injected i.t. at equimolar doses with morphine did not produce similar convulsive behavior. DALA and methadone rather produced pronounced spinal catalepsy. It was concluded: (1) that the spinal convulsive action of morphine is not mediated by specific opiate receptors; and (2) that the spinal cord may be one of the sites where high doses of systemically administered morphine may produce convulsions.

Cataleptic effects of opiates following intrathecal administration

Intrathecal (i.t.) administration of d-ala 2-methionine-enkephalinamide (DALA) and methadone induces pronounced hindlimb catalepsy in rats. DALA is more potent than methadone in inducing this behavior and catalepsy induced by both compounds is partially blocked by prior treatment with naltrexone. Intrathecal morphine induces convulsive hindlimb activity at doses of 25, 100 and 400 μg. However, only the highest dose produces indications of cataleptic behavior. It is suggested that whereas the convulsive behavior induced by i.t. morphine is not mediated by specific opiate receptors, catalepsy induced by all 3 compounds is.

Depression of neuronal activity in the hypothalamic ventromedial nucleus of the rat following microinjection of morphine in the amygdala or the periaqueductal gray

The effects of morphine administered intravenously and intracerebrally in the cortical amygdala and periaqueductal gray were examined on spontaneous neuronal activity in the hypothalamic ventromedial nucleus in both intact and castrated adult male rats. Spontaneous extracellular single unit activity in the ventromedial nucleus was significantly faster in chronically castrated (19–23 days) rats compared with intact control rats (6.0± 1.1 and2.5 ± 0.3 spikes s. respectively). Neurons in the ventromedial nucleus exhibited a significant attenuation of neuronal activity following the intravenous administration of morphine: the maximal per cent decrease (to 25% of the control unit activity) was the same in both castrated and intact rats, but cell firing in castrated rats was affected more at lower doses of morphine. When microinjected bilaterally in the cortical amygdala or periaqueductal gray (5μg/site). morphine produced the same maximal depression of unit activity in the ventromedial nucleus as when administered intravenously. The time required to significantly attenuate unit activity in the ventromedial nucleus was the same (3 min) whether morphine was administered intravenously or bilaterally in the periaqueductal gray. When microinjected bilaterally in the cortical amygdala, the depressant effect of morphine on cell tiring in the ventromedial nucleus was significant first at 10 min. These data correlate well with the time courses for depression of serum levels of luteinizing hormone produced by morphine microinjected in the same doses in the same extrahypothalamic sites in the rat. In view of the relatively high levels of specific opiate receptor binding in both the periaqueductal gray and amygdala, this report further supports a role for modulation by extrahypothalamic areas of opioid-induced changes in the functional activity of the hypothalamic-pituitary axis, perhaps via the ventromedial nucleus.

Age difference in endogenous opiate modulation of short photoperiod-induced testicular regression in golden hamsters

Effects of age and naloxone on testicular function were studied in golden hamsters exposed to short photoperiods. Subjection of hamsters to short photoperiods of 6 h light: 18 h darkness for 6 weeks led to testicular regression in young adult (5-6 months) or middle-aged (11-12 months) golden hamsters but not in prepubertal hamsters of 1-2 months of age. The middle-aged hamsters had decreased testis width by week 4 of treatment and the young hamsters by week 5. Daily injection of naloxone at the time of 'lights on' partially prevented testicular regression in young and middle-aged hamsters but the extent of regression was significantly greater in the middle-aged animals. Plasma LH and FSH concentrations were significantly reduced in hamsters placed in short photoperiods regardless of age or testicular weight, while naloxone treatment significantly increased the LH concentrations in all age groups. Plasma beta-endorphin-like immunoreactivity was significantly increased by short photoperiod or older age. These results indicated that (a) the sensitivity of the testicular suppression to short photoperiod increases as a function of age, (b) naloxone, a specific opiate receptor blocker, can partially prevent short photoperiod-induced testicular regression and (c) ageing and short photoperiods increase beta-endorphin-like immunoreactivity. It is concluded that the opiate system may be involved in ageing and photoperiod regulation of reproductive function.

Effect of naloxone on pancreatic and gastric endocrine function in response to carbohydrate and fat-rich test meals

The present study was designed to determine the effect of naloxone, a specific opiate receptor antagonist, on postprandial levels of insulin, glucagon, pancreatic polypeptide (PP), somatostatin-like immunoreactivity (SLI) and gastrin in response to carbohydrate and fat-rich test meals in a group of 6 healthy volunteers. The addition of naloxone to a meal consisting of 50 g sucrose dissolved in 200 ml water augmented the rise of plasma insulin levels significantly during the first 30 min after its ingestion and reduced the decrease of plasma glucagon. During the ingestion of a fat-rich meal in form of 200 ml cream naloxone reduced the rise in plasma insulin and pancreatic polypeptide and elevated glucagon levels during the last 30 min of the experimental period. When sucrose was dissolved in 200 ml cream the addition of naloxone augmented the postprandial rise of insulin levels between 15 and 60 min after ingestion of the meal and elicited an increase of plasma SLI and PP levels throughout the entire experimental period which indicates that post-prandial levels of insulin, glucagon, PP and SLI are modulated via endogenous opiate receptors during the ingestion of carbohydrate and fat test meals and that this effect depends on the composition of the ingested nutrients. These data raise the possibility that endogenous opiates participate in the regulation of postprandial insulin, glucagon, somatostatin and pancreatic polypeptide release not only in certain disease states as demonstrated recently for insulin secretion in type II diabetes mellitus but endogenous opiates may also be of importance under physiological conditions.

Effects of morphine on ionic currents in frog node of Ranvier

The effects of externally or internally applied morphine hydrochloride on the node of Ranvier of the frog were studied under current and voltage clamp conditions. Externally applied morphine in a concentration of 0.5-1 mM prolonged the action potential and the absolute refractory period. It inhibited the repetitive response of sensory fibres to long-lasting depolarizing pulses. Externally applied morphine was more effective in depressing the steady state K current than the peak Na current. When added to the internal medium (by diffusion from the cut ends of the fibre) morphine had a stroger effect on the peak Na current. Morphine did not alter the kinetics of Na activation but increased the time constants of development or removal of Na inactivation by a factor of about 1.2. Morphine reduced both the fast and slow phase of the inward K tail currents recorded in Ringer with 30 mM K. Of the two components (g Kf1 and g Kf2) of fast K conductance described by J.M. Dubois (1981, J. Physiol. 318, 297) only g Kf2 was affected. The morphine antagonist naloxone in a concetration of 0.1 mM completely and reversibly abolished the component g Kf2 of the fast K conductance. Naloxone did not antagonize the effect of morphine. These findings show that there are no specific opiate receptors in the membrane of peripheral nerves.

Nalorphine: actions at an opiate receptor on frog skeletal muscle fibers.

Intracellular microelectrode studies were conducted to investigate the actions of the partial agonist-antagonist nalorphine at an opiate receptor on functional frog skeletal muscle fiber membranes. In high bath concentrations (greater than or equal to 10(-4) M), nalorphine alone produces agonist actions similar to the "full" opiate agonists. These actions were (i) to depress both the sodium and potassium (gNa and gK) conductance increases due to electrical stimulation by a nonspecific local anestheticlike mechanism and (ii) to depress gNa by a specific opiate receptor mediated mechanism. In a much lower bath concentration (1 X 10(-8) M) nalorphine acts to antagonize the specific opiate receptor mediated depression of gNa produced by the "full" agonist meperidine. Thus in this preparation nalorphine, "the partial antagonist," has the same actions as naloxone, which is often considered to be a full antagonist. The quantitative differences observed in the effects of these two opiate antagonists are discussed.

Differential cardiovascular effects mediated by mu and kappa opiate receptors in hindbrain nuclei

To further investigate the role of opioid peptides and specific opiate receptor subtypes in central cardiovascular regulation by hindbrain nuclei, mu (D-Ala 2,MePhe 4,Gly-ol 5 enkephalin, DAGO), delta (D-Ala 2,D-Leu 5 enkephalin, DADL) or kappa (MRZ 2549) agonists were microinjected into hindbrain nuclei of spontaneously or artificially respired, pentobarbital-anesthetized rats. In the nucleus tractus solitarius (NTS), DAGO and DADL (0.3 nmol) elicited pressor responses and tachycardia. MRZ (3.0–16 nmol) depressed blood pressure in spontaneously breathing rats, but accelerated heart rate in artificially ventilated animals. Blood pressure and heart rate of spontaneously breathing animals were not altered following nucleus ambiguus (NA) injection of DAGO or DADL (0.3 nmol), but were elevated in artificially respired animals; MRZ (3.0–10 nmol) injected into the NA depressed blood pressure in both groups. These data suggest that in the absence of respiratory depression, NTS and NA mu receptors mediate pressor responses and tachycardia; kappa receptors in the NA mediate a decrease in blood pressure but cardioacceleration in the NTS.

Morphometric evaluation of the effect of opioid peptides on cysteamine-induced ulcers in rats

Morphometry was used to study the action of an enkephalin analog and beta-endorphine on the duodenal mucosa in rats with an experimental ulcer induced by cysteamine. Enkephalin produced a more powerful protective action than endorphine. The antiulcerous action was manifested in the diminution of dystrophic changes, redistribution of inflamed cells with an increase in the lymphocyte and monocyte counts, and in the reduction of the number of tissue macrophages and histocytes. Administration of opioids provoked a particularly marked increase in the eosinophil count in the duodenal mucosa. All these effects were abolished by naloxone. It is concluded that the tissue effects of opioids are mediated by specific opiate receptors.

Hypothalamic regulation of the cardiovascular and respiratory systems: role of specific opiate receptors.

Experiments were designed to evaluate the role of mu and delta opiate receptors in central cardiovascular control in the hypothalamic nucleus preopticus medialis of rats anaesthetized with pentobarbitone. The highly selective mu opiate receptor agonist D-Ala2-MePhe4-Gly5-ol-enkephalin was extremely potent in eliciting hypotension and bradypnoea; tachycardia was elicited by a low dose (0.064 nmol), but not by higher doses (0.64-6.4 nmol). Other selective mu receptor agonists (morphine sulphate, morphiceptin) caused tachycardia at lower doses (0.64, 6.4 nmol), hypotension and bradypnoea after the highest dose (64 nmol). The relatively selective delta receptor agonist D-Ala2-D-Leu5-enkephalin caused profound bradypnoea and hypotension at the high dose (64 nmol), tachycardia after the lowest dose (0.64 nmol), but bradycardia was found during the hypotension induced by the high dose (64 nmol). All of the opiate/opioid effects were reversed by naloxone (0.5 mg kg-1, i.v.). It is concluded that mu receptors may mediate the cardiovascular and respiratory effects of opiates and opioid peptides in the nucleus preopticus medialis of the rat.

Effects of naloxone and an enkephalin analog on serum prolactin, cortisol, and gonadotropins in the chimpanzee.

To assess a possible regulatory influence of opioids upon anterior pituitary function in the chimpanzee, we evaluated the effects of the specific opiate receptor antagonist naloxone and the agonistic enkephalin analog [D-Ala2, MePhe4,Met(o)-ol]enkephalin (FK 33-824; Sandoz) on serum levels of PRL, cortisol, FSH, and LH. Under ketamine anesthesia, the following were administered by iv injection during the early follicular phase of successive menstrual cycles in nine female chimpanzees: naloxone (10 mg; n = 7) or saline vehicle (n = 7) randomly assigned in the first two cycles, FK 33-824 0.25 mg (n = 3) in the third cycle, FK 33-824 0.50 mg (n = 4) in the fourth cycle, and FK 33-824 (0.50 mg) immediately preceded by naloxone (10 mg; n = 4) in the last cycle. Five pretreatment and 12 posttreatment serum samples were obtained at 10- to 15-min intervals for subsequent RIA. Naloxone caused a significant reduction in PRL levels from a pretreatment mean of 29.3 ng/ml to a mean of 11.1 ng/ml at 180 min. Values from 60-180 min were significantly below the saline control group at comparable times. A dose-related increment in PRL levels was seen after FK 33-824 administration, with mean peak values at 30 min of 61.0 and 92.3 ng/ml after the low and high doses, respectively. Naloxone pretreatment markedly attenuated the response to high dose FK 33-824. Cortisol levels rose in all groups throughout the study period, a presumed effect of the ketamine anesthesia. Compared to the saline group, no effects of FK 33-824 were observed. Naloxone, given alone or with FK 33-824, had a small, but significant, stimulatory effect on cortisol from 60-120 min posttreatment compared to the control group. Naloxone caused a significant increment in LH levels from a pretreatment mean of 11.7 micrograms/dl to a peak of 19.1 micrograms/dl at 30 min and in FSH level from 33.2 micrograms/dl before therapy to 40.0 micrograms/dl at 45 min. There was no influence of FK 33-824 on gonadotropin levels, although the high dose did blunt the response to naloxone. Taken together, these effects suggest that opiate agonists and endogenous opioid pathways may modulate anterior pituitary function in the chimpanzee, as in man.

Beneficial Actions of Nalorphine during Hemorrhagic Shock in Cats

Endogenous opiates have been reported to have detrimental effects on the circulatory system during hemorrhagic shock. However, the specific opiate receptor subtype which mediates these actions has not been defined. In the present study, we have utilized the mixed agonist/antagonist, nalorphine (N-allylnormorphine), which exhibits kappa (kappa) and sigma (sigma) receptor agonism as well as mu (mu) receptor antagonism, to investigate the role of the mu receptor in hemorrhagic shock. Nalorphine (2 mg/kg) produced no significant changes in any observed experimental variable in sham-shocked animals. Shocked animals treated with nalorphine (2 mg/kg) maintained significantly higher final mean arterial blood pressures (MABP) than animals which received only vehicle (102 +/- 3.8 vs 61 +/- 6.6 mm Hg, respectively, p less than 0.001). In addition, nalorphine significantly reduced the rise in plasma MDF activity observed in untreated hemorrhaged animals (42 +/- 3.0 vs 59 +/- 4 U/ml, p less than 0.02). Our results support a significant role for the mu receptor in the deleterious actions of endogenous opioids during hemorrhagic shock.

NALOXONE, A SPECIFIC OPIOID ANTAGONIST, REVERSES CHRONIC IDIOPATHIC CONSTIPATION

Two patients with long-standing idiopathic chronic constipation, which responded only to large daily doses of laxatives and additional suppositories and enemas, were treated with the specific opioid antagonist, naloxone, on a single-blind crossover basis. Both patients responded to naloxone treatment, with increased passage of faeces and increased wet and dry faecal weight. Although naloxone is poorly absorbed after oral administration, there was a positive response during oral as well as intravenous treatment, suggesting that the primary effect of naloxone is at specific opiate receptor sites in the myenteric plexus and other neural and endocrine cells of the intestinal wall.