Chronic Morphine-treated Rats Research Articles

Changes in hypothalamic paraventricular nucleus catecholaminergic activity after acute and chronic morphine administration

The participation of hypothalamic noradrenaline in the expression of neuroendocrine signs of morphine withdrawal has been proposed. The present study in rats examined: (1) the relationships between corticosterone secretion and the possible modifications in noradrenaline and dopamine content and turnover in the hypothalamic paraventricular nucleus after acute and chronic morphine administration; (2) the changes in cyclic adenosine monophosphate (cAMP) levels in the paraventricular nucleus after the same treatments. The results showed that acute morphine injection in control rats increased corticosterone release, 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) production, and noradrenaline turnover. Dopamine turnover in the paraventricular nucleus was decreased and the cAMP levels remained unchanged. In chronic morphine-treated rats, there was no elevation in noradrenaline turnover or in corticosterone secretion, indicating that tolerance developed to the acute effects of the opioid. Correspondingly, no alterations in dopamine turnover were observed when chronic morphine-treated rats were compared with control rats acutely injected with morphine. cAMP levels in the paraventricular nucleus were unchanged during the tolerant state. The results raise the possibility that noradrenergic afferents play a significant role in the alterations of paraventricular nucleus function and pituitary–adrenal axis activity in response to acute and chronic morphine and suggest that these modifications are not mediated through adenylate cyclase activation. The present data provide further support for the idea of adaptive changes in noradrenergic neurons projecting to the paraventricular nucleus during chronic morphine exposure.

Differential regulation of corticotropin-releasing factor and vasopressin in discrete brain regions after morphine administration: correlations with hypothalamic noradrenergic activity and pituitary-adrenal response.

The changes in the content of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) in discrete brain nuclei during chronic opioids administration have not been well established. We evaluated the effects of acute and chronic morphine administration on the content of CRF and AVP in different hypothalamic and extrahypothalamic (bed nucleus of the stria terminalis, BNST) nuclei in rats. Concomitantly, changes in hypothalamic noradrenaline (NA) turnover [estimated by the 3-methoxy-4-hydroxyphenylethyleneglycol MHPG/NA ratio] and in plasma corticosterone release (as a marker of the activity of the hypothalamus-pituitary-adrenal axis) were determined. Male rats were implanted with placebo (naïve) or morphine (tolerant) pellets for 7 days. On day 8, groups of rats received an acute injection of either saline i.p. or morphine (30 mg/kg i.p.) and were sacrificed 30 min later. Acute morphine injection to naïve rats increased both the release of corticosterone and the hypothalamic NA turnover. CRF and AVP showed no modifications in the paraventricular nucleus (PVN) or in the median eminence (ME). CRF content decreased in the ventromedian nucleus (VMN) and increased in the BNST, but did not change in the arcuate nucleus (AN). AVP was elevated in the supraoptic nucleus (SON) but not changed in the suprachiasmatic nucleus (SCN). In chronic morphine-treated rats, there was a pronounced decrease in the NA turnover and in the release of corticosterone, which indicates that tolerance develops to the acute effects of morphine. Correspondingly, CRF and AVP were enhanced in the PVN and decreased in the ME, when compared with naïve rats injected with morphine. CRF content was decreased in the AN and in the BNST, but increased in the VMN. The AVP content was decreased in the SON, and no modifications were seen in the SCN. The present study shows that, in addition to the modifications in corticosterone secretion and in hypothalamic NA turnover, chronic morphine administration produces a complex response in the CRF and AVP systems. These modifications might contribute to the behavioral, emotional and neuroendocrine alterations produced during opioid tolerance.

Multiple effects of long-term morphine treatment on postsynaptic β-adrenergic receptor function in hippocampus: an intracellular analysis

We previously reported that β-adrenergic receptors are increased in cerebral cortex and hippocampus in rats treated chronically with morphine and subsequently down-regulated after morphine withdrawal [22,23]. The changes in receptor density in hippocampus were accompanied by a corresponding super- and subsensitivity, respectively, in β-adrenergic responsiveness, as assessed electrophysiologically by measuring the ability of isoproterenol to augment population spike responses in the slice. In this study, we compared the ability of isoproterenol to reduce the Ca 2+-activated K + slow afterhyperpolarization (slow AHP) in pyramidal neurons in hippocampal slices from opiate-naive and chronic morphine-treated rats to determine whether such changes in β-adrenergic receptor function are localized postsynaptically. Chronic treatment of rats with morphine produced a 3.5-fold parallel shift to the left in the concentration-response curve for isoproterenol and reduced the EC 50 from 4.8 ± 1.3 to 1.4 ± 0.5 nM. In contrast, sensitivity and maximal responsiveness to isoproterenol was markedly decreased in pyramidal neurons recorded in slices from morphine withdrawn animals. The concentration-response curves for inhibition of the slow AHP by carbachol or forskolin were not affected by chronic morphine treatment. However, blockade of the slow AHP by forskolin was significantly reduced in pyramidal neurons studied after morphine withdrawal. These data suggest that the increase in electrophysiological responsiveness to β-adrenergic receptor stimulation found in hippocampus after chronic morphine treatment most likely resulted from an up-regulation in postsynaptic membrane receptors, whereas alterations occurring beyond the receptor level may be involved in the desentization that is associated with morphine withdrawal.

The interaction of the mu-opioid receptor and G protein is altered after chronic morphine treatment in rats.

The interaction of mu-opioid receptors and G proteins after chronic morphine treatment was investigated in rats. Male Sprague-Dawley rats (200-260 g) were rendered tolerant to morphine by i.p. injections of increasing doses of morphine twice daily for 4 or 6 days. During this period, there was a time-dependent increase in the AD50 values for morphine to inhibit the tail-flick response. In addition, in vitro mu-opioid receptor binding to midbrain P2 membranes from these animals revealed that the ability of 10 mumol/l Gpp(NH)p (guanyl-5'-yl imidodiphosphate) to decrease [3H]DAMGO (Tyr-D-Ala-Gly-MePhe-Gly-ol) binding affinity, i.e., the ratio Kd(+Gpp(NH)p)/Kd(-Gpp(NH)p), decreased significantly from the control value of 3.68 +/- 0.40 to 2.37 +/- 0.35 after 6 days of morphine treatment (P < 0.05). The ability of DAMGO to stimulate low Km GTPase activity was also investigated. The EC50 significantly increased from 2.7 +/- 1.1 x 10(-8) mol/l in the control group to 10.8 +/- 1.5 x 10(-8) mol/l after 4 days of morphine treatment and was further increased to 13.5 +/- 2.1 x 10(-8) mol/l after 6 days of morphine treatment. The maximal stimulation by DAMGO decreased significantly from 18.0 +/- 1.7% to 12.8 +/- 1.6% after 6 days of morphine treatment. These results indicate that the interaction between mu-opioid receptors and G proteins had been altered after chronic morphine treatment.

Concurrent nimodipine attenuates the withdrawal signs and the increase of cerebral dihydropyridine binding after chronic morphine treatment in rats.

The effect of chronic administration of dihydropyridine calcium channel antagonist nimodipine (1 mg/kg/day) given concurrently with morphine on the signs of morphine withdrawal and on the [3H]nitrendipine binding in the rat brain has been investigated. Chronic morphine administration in increasing daily doses from 20 mg/kg to 70 mg/kg for 24 days and consequent withdrawal for 24 h induced loss of body weight, wet dog shakes, episodes of writhing and yawning behaviour. The density of [3H]nitrendipine binding was elevated in the cortex and limbic structures but not in the striatum after chronic morphine treatment. Chronic concurrent administration of nimodipine prevented the loss of body weight and reduced the scores of wet dog shakes and writhing, but did not affect yawning behaviour at 24 h after morphine withdrawal. The concurrent nimodipine treatment also prevented the rise in the density of central dihydropyridine binding sites which occurred upon chronic morphine treatment. These results suggest that chronic nimodipine treatment attenuates the development of the withdrawal signs which occur upon the termination of chronic morphine treatment by preventing the up-regulation of the central dihydropyridine-sensitive binding sites.

Extraneuronal noradrenaline in the prefrontal cortex of morphine-dependent rats: tolerance and withdrawal mechanis

The changes in extracellular concentrations of noradrenaline (NA) in the prefrontal cortex of morphine-dependent rats were studied by microdialysis following an acute morphine challenge and during naloxone-precipitated withdrawal. Animals were implanted with morphine- or placebo-containing pellets for 5 days. In control rats a challenge dose of morphine (5 mg/kg s.c) induced a maximum decrease in NA output of about 45% of pre-drug levels. In contrast, morphine challenge had no effect on extraneuronal NA concentrations in morphine-implanted animals. In control animals, naloxone (2 mg/kg i.p.) produced no behavioral effect nor changed NA levels. However, in morpine-dependent animals naloxone suddenly increased extraneuronal NA by 175% of baseline dialysate levels in the first sample after the injection and precipitated a morphine-withdrawal symptomatology that paralleled the changes in NA output. Thus, chronic morphine treatment in rats results in the development of tolerance to the acute inhibitory effect of morphine on extraneuronal NA and is associated with a stimulation of prefrontocortical NA output during naloxone-precipitated withdrawal.

Modulation of morphine-induced sensitization by endogenous κ opioid systems in the rat

Sensitization to both the motor stimulant and mesolimbic dopamine-releasing effects of morphine were studied in animals chronically treated with morphine and those that had received the κ opioid receptor antagonist, nor-binaltorphimine (nor-BNI) prior to the commencement of morphine treatment. Rats were pretreated with either nor-BNI (30 μg; i.c.v.) or its vehicle and then received injections of morphine for 10 days. Locomotor activity and microdialysis studies were then conducted 3 and 30 days after tremination of the chronic morphine treatment. In chronic morphine-treated rats, sensitization developed to both the motor stimulatory effects of morphine and the mesolimbic dopamine-releasing effects of this drug. Sensitization was observed 3 and 30 days after termination of morphine treatment. In animals pretreated with nor-BNI, sensitization to both the motoric and dopamine-releasing effects of morphine was significantly greater than that of chronic morphine-treated rats. These results suggest that endogenous κ opioid systems play an important role in morphine-induced sensitization and that manipulations of these systems can markedly influence both its behavioral and neurochemical expression.

Changes in preganglionic sympathetic nerve function following chronic morphine treatment in rats

1. The effects of acute or chronic morphine treatment on the changes in blood pressure and pulse rate in response to ganglionic stimulation or blockade and to vagal stimulation, and of isolated atria to field stimulation or noradrenaline, were studied. 2. In pithed rats, intravenously injected hexamethonium significantly depressed the blood pressure responses to sympathetic nerve stimulation. The ganglionic blocking effects of hexamethonium were significantly greater in chronically morphine-treated rats, but were not significantly affected by acute morphine administration in naive animals. 3. Intravenous administration of nicotine dose-dependently increased blood pressure and pulse rate. The magnitudes of these changes were not significantly affected by acute or chronic morphine pretreatment. 4. Studies with rat isolated atrial preparations revealed that the changes in atrial contractile rate and force in response to noradrenaline or field stimulation were not influenced by either acute or chronic morphine treatment. 5. Cervical vagal stimulation produced voltage- or frequency-dependent decreases in pulse rate and blood pressure. The responses were not significantly affected by chronic morphine treatment. 6. These findings suggest that the site of the changes in sympathetic function following prolonged exposure to the opiate appears to be on the preganglionic nerve fibres.

Opioid receptor subtypes in the supraoptic nucleus and posterior pituitary gland of morphine-tolerant rats

Morphine, given acutely, inhibits oxytocin secretion in adult female rats, but chronic intracerebroventricular infusion for five to six days induces tolerance and dependence in the mechanisms regulating oxytocin secretion. One explanation for tolerance could be that there is a loss of opioid receptors. To test this hypothesis cryostat sections of selected brain regions and the pituitary, from six control and six intracerebroventricular morphine-infused rats, were processed for quantitative in vitro receptor autoradiography. [ 3H]Etorphine or [ 3H](−)-bremazocine were used as ligands, and DAGO, DPDPE and U50,488H as selective displacers from μ-, δ-, and κ-receptors, respectively. Control incubations had naloxone determined specificity. The supraoptic nucleus (site of oxytocin-secreting magnocellular perikarya) contained both μ- and κ-receptors in control rats (mean ± S.E.M. binding of μ-selective [ 3H]etorphine was 91.8 ± 25.4 fmol/mg of tissue, and of κ-selective [ 3H](−)-bremazocine was 130.4 ± 25.6 fmol/mg). Chronic morphine treatment caused a 83.9% decrease in binding in μ-selective conditions ( P < 0.05), but no significant change in κ-selective binding. In the median preoptic nucleus (which projects to the supraoptic nucleus) mean ± S.E.M. binding of [ 3H]etorphine decreased by 77.0% ( P < 0.01) in chronic morphine-treated rats, from the control value of 76.2 ± 9.8 fmol/mg of tissue. In the posterior pituitary gland (site of the terminals of the oxytocin-secreting magnocellular perikarya) binding with [ 3H](−)-bremazocine in controls was over 90% lower than in the supraoptic nucleus. No changes followed chronic morphine treatment. Thus chronic morphine exposure reduces the numbers of available μ-receptors in the supraoptic nucleus, and of opioid receptors in the median preoptic nucleus, perhaps accounting for morphine-tolerance in relation to oxytocin secretion.

The binding of 3H-(3-MeHis 2) thyrotropin releasing hormone to brain and pituitary membranes of morphine tolerant-dependent and abstinent rats

The effect of chronic administration of morphine and subsequent withdrawal on brain and pituitary receptors for thyrotropin releasing hormone (TRH) was investigated in Sprague-Dawley rats. The rats were implanted subcutaneously with four morphine pellets (each containing 75 mg of morphine free base) during a 3-day period. Placebo pellets, which contained all the excipients of morphine pellets except the morphine, were implanted in rats which served as controls. Both tolerance and physical dependence on morphine have been shown to develop as a result of this procedure. TRH receptors were labeled with 3H-(3-MeHis 2) TRH (MeTRH). 3H-MeTRH bound to brain membranes at a single high affinity site with B max (receptor density) value of 24.6±2.2 fmol/mg protein and K d (apparent dissociation constant) value of 3.7±0.4 nM. The binding of 3H-MeTRH to five regions of the brain namely, hypothalamus, cortex, striatum, midbrain and pons + medulla, as well as pituitary was also investigated. The binding of 3H-MeTRH to pituitary membranes was increased during the development of tolerance, whereas the binding to membranes prepared from different brain regions was unaffected. Serum concentration of triiodothyronine (T 3) and thyroxine (T 4) were found to be lower in chronic morphine-treated rats when compared to placebo-treated rats, however, serum TSH level remained unaltered. Twenty-four hours after the removal of morphine pellets (natural withdrawal), the binding of 3H-MeTRH to pons + medulla membranes was greater than in placebo control group. Naloxone-precipitated withdrawal produced results which were qualitatively similar to those obtained in rats from which pellets had been removed. The results suggest that the development of tolerance to morphine may be associated with changes in the pituitary-thyroid axis.

Arterial catecholamine levels in morphine-treated rats subjected to sympathetic nerve stimulation.

1. The effect of acute or chronic morphine treatment on the changes in arterial noradrenaline and adrenaline levels in response to sympathetic nerve stimulation was studied in rats. 2. Rats which had been chronically treated with morphine in their drinking fluid for 21 days were shown to be morphine-tolerant, as revealed by the tail-immersion test for analgesia. 3. It was found that animals given either acute or chronic morphine treatment had similar basal concentrations of arterial catecholamines to their controls. 4. Sympathetic nerve stimulation produced significant increases in arterial noradrenaline and adrenaline levels in both the control and morphine-treated animals. However, the degree of arterial noradrenaline elevation was significantly less in morphine-tolerant animals. 5. This phenomenon was not observed in acutely morphine-treated rats or at 2 weeks following opiate withdrawal in animals which had been treated previously with morphine for 3 weeks. 6. The findings suggest that chronic morphine treatment in rats not only leads to opiate tolerance but also reduces catecholamine release in response to sympathetic nerve stimulation.

Intravenous morphine infusion (IMF) to drug-naive, conscious rats evokes bradycardic, hypotensive effects, but pressor actions are elicited after IMF to rats previously given morphine.

Hemodynamic (blood pressure and heart rate) responses of conscious drug-naive rats were studied following intravenous (i.v.) infusion of sterile saline, morphine sulphate, and then naloxone hydrochloride, as well as of other groups previously injected with morphine sulphate. Those groups chronically given morphine sulphate received twice daily injections of morphine sulphate (5 mg/kg, s.c. per injection) for 3 or 6 days before testing with the i.v. infusion of morphine sulphate. Drugs were infused (135 microL/min) through an indwelling femoral venous catheter via a Harvard infusion pump, and blood pressure was recorded from the abdominal aorta via a femoral arterial catheter. Other pretreatment studies were done to determine the receptor mechanisms mediating the blood pressure responses of drug-naive and chronic morphine-treated rats, whereby equimolar doses (0.32 mumol) of specific receptor antagonists were given as a bolus i.v. injection 5 min after saline but before subsequent infusion with morphine sulphate. Intravenous infusion of morphine sulphate (7.5 mg/kg total over 15 min) to drug-native rats caused a transient but precipitous fall in mean arterial pressure and mean heart rate with an associated rise in mean pulse pressure; these effects were blocked in other groups pretreated with atropine. Interestingly, however, rats chronically injected with morphine sulphate for 3 days previously evoked a transient pressor response when subsequently infused i.v. with morphine sulphate, actions that were blocked in other groups when pretreated i.v. with 0.32 mumol of phentolamine, yohimbine, prazosin, or guanethidine. A greater and persistent pressor response occurred following morphine infusion to groups of rats previously injected over 6 days with morphine sulphate, which was associated with tachycardia during the later stages of the 15-min morphine sulphate infusion period. The prolonged pressor and tachycardic responses of this 6-day chronically injected group were completely blocked in another group pretreated i.v. with both phentolamine and propranolol (0.32 mumol). The results suggest that morphine sulphate infusion to conscious, drug-naive rats evokes classical hypotensive effects due to decreases in mean heart rate caused by activation of parasympathetic vagal activity. With 3 or 6 days of chronic morphine sulphate administration beforehand, subsequent i.v. infusion of morphine sulphate evoked pressor actions felt to be caused by a progressive activation of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 400 WORDS)

Plasma, cardiac tissue and brain morphine concentrations in acute and chronic morphine-treated rats.

1. The plasma, cardiac tissues and brain morphine concentrations in rats after acute or chronic morphine treatment were measured by high-performance liquid chromatography. 2. Morphine concentrations in plasma and cardiac tissues were found to be significantly higher than those in brain after acute morphine injection. However, after chronic oral administration, morphine concentrations in plasma, cardiac tissues and brain were similar. 3. Brain concentrations of morphine following chronic administration were higher than those obtained after acute administration although concentrations in plasma and cardiac tissues were lower.

Chronic morphine increases μ-opiate receptor binding in rat brain: a quantitative autoradiographic study

Quantitative autoradiography was used to show the locations of μ-opiate receptor binding sites which are upregulated following chronic morphine treatment in rats. A saturating concentration of the μ-specific ligand [ 3 H] d- ala 2-N- methyl-Phe 4 , Gly-ol 5-enkephalin was used to label sites in slide-mounted sections through one level of the thalamus in rats implanted subcutaneously with morphine pellets for 5 days. In vitro binding and autoradiography showed the largest increase in binding in the hypothalamus, especially the ventromedial nucleus (155%), with smaller increases in the basolateral and medial amygdaloid nuclei and the striatum. The set of structures showing the upregulation appears to be a subset of those upregulated by opiate antagonists, but there appears to be no correlation of the μ-sites showing upregulation with other anatomical features of the brain opiate system. The physiological significance of the upregulation is not known at present.

Ventricular histamine concentrations in naive and morphine-treated rats during acute myocardial ischaemia.

The ventricular histamine concentrations of naive and morphine-treated rats subjected to acute left coronary artery ligation were examined. In naive animals, there was a significant increase in the right ventricular histamine level at 5 min following ligation, but not at 3 or 10 min. Left ventricular histamine concentrations tended to decrease, but the changes were not statistically significant. In shamoperated rats, neither acute nor chronic morphine treatment significantly altered either right or left ventricular histamine levels. Acute morphine treatment also did not significantly affect the ventricular histamine content at 5 min following coronary artery ligation. However, both right and left ventricular histamine concentrations were found to be significantly lower in chronic morphine-treated rats than in the naive animals when they were subjected to acute myocardial ischaemia. If the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia is accepted, the present findings suggest that the previously reported decreased incidence and delayed onset of early ventricular arrhythmias induced by acute left coronary artery ligation in chronic morphine-treated rats may be attributed to the reduced ventricular histamine concentrations.

Dopamine receptor subsensitivity in the substantia nigra after chronic morphine treatment in rats

Several classes of 5-HT and dopamine (DA) receptor binding sites, and the levels of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), DA and dihydroxyphenylacetic acid (DOPAC) were examined in various brain regions 24 h after a 10-day treatment with morphine (2 × 15 mg/kg s.c. daily) in adult rats. Quantitative autoradiography of receptor binding sites revealed only a significant reduction of [ 3H]SCH-23390 and [ 3H]spiperone binding to D-1 and D-2 sites, respectively, in the substantia nigra pars compacta of morphine-treated rats. 5-HT and 5-HIAA levels remained unchanged in the substantia nigra and striatum, but the nigral levels of DA and DOPAC and the levels of DOPAC in the striatum were reduced significantly by morphine treatment. Apomorphine, at a dose (0.05 mg/kg s.c.) known to stimulate DA autoreceptors, decreased nigral and striatal DOPAC levels in controls but not in morphine-treated rats. It is concluded that chronic morphine treatment probably induces a down regulation of nigral D-1 and D-2 binding sites and reduces the negative feed-back mechanisms triggered by DA autoreceptors.

Cardiovascular responses to acute myocardial ischaemia in morphine-dependent rats.

1. The cardiovascular responses to acute myocardial ischaemia were studied in opiate-dependent animals before and after 2 weeks morphine withdrawal. 2. Rats were treated with morphine sulphate in drinking water for 2, 3 or 5 weeks. The development of morphine tolerance and dependence was verified by the tail-immersion test for analgesia and the naloxone-precipitated withdrawal syndrome, respectively. 3. Acute left coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate and ventricular tachycardia or fibrillation in anaesthetized naive rats. 4. Chronic morphine treatment did not alter the haemodynamic responses to coronary artery ligation. However, a significantly lowered incidence, and prolonged time of onset, of ventricular arrhythmias was found in 3 and 5 week morphine-treated rats. This phenomenon did not occur in animals receiving morphine for 2 weeks and in a 3 week morphine-treated group which was subsequently withdrawn for 2 weeks. 5. It is suggested that the decreased occurrence of early ventricular arrhythmias resulting from acute myocardial ischaemia in chronic morphine-treated rats may be related to the degree of opiate tolerance and dependence.

Gastric acid secretory responses to cholinergic and histaminergic stimulation in chronic morphine-treated rats

The effects of chronic morphine administration on cholinergic and histaminergic activities were evaluated in rats by observing their gastric acid secretory responses to secretagogues. The responses of in-vivo perfused stomachs to 2-deoxy-D-glucose or pentagastrin, and of the isolated gastric mucosa to histamine or bechanechol, were not significantly different between naive and chronic morphine-created animals. It is suggested chat the chronic morphine-created rats exhibit normal cholinergic and histaminergic activities as well as receptor sensitivities to acetylcholine and histamine. Many investigations have demonstrated chat chronic administration of morphine leads not only to the development of tolerance and physical dependence, but also to some physiological alterations. However, the chronic effects of the narcotic on cholinergic activity appear to be complex (Crossland and Slater, 1968; Bhargana and Hay, 1972; Jhamandas and Sutak, 1974; Mohanakumar and Sood, 1983). It also remains unclear whether chronic administration of the opiate will cause changes in the activity of the histamine-containing cells or in receptor sensitivity to histamine. The present study examines the effects of chronic morphine treatment on cholinergic and histaminergic activities in rats by observing the gastric acid secretory responses of in-vivo perfused stomachs and isolated mucosal preparations Co secretagogues.

Suppression of the induction of delayed hypersensitivity in rats by repetitive morphine treatments

Previous in vitro experiments suggest that lymphocyte function may be altered in the presence of opiates. The effect of morphine treatment upon specific T lymphocyte function in vivo was investigated in rats. Following morphine treatment, rats were incapable of responding to immunization with the T-dependent antigens of Mycobacterium bovis, strain BCG. The absence of a delayed hypersensitive skin response to tuberculin in chronic morphine-treated rats supports the hypothesis that opiates may interact with the cells of the immune system. A potential communication between the nervous system and cells of the immune system is proposed.

Effects of morphine on brainstem neurones in naive and chronic morphine-treated rats, and effects of PCPA

Rats were made dependent on morphine by adding the drug to both their food and drinking water for 7 days. Following withdrawal of morphine after 5 days of exposure, obvious abstinence effects were seen. Responses of brain stem neurones to microiontophoretically applied morphine were examined in rats after chronic exposure to morphine, as well as 48 hr after withdrawal. These responses were compared with those obtained in naive control rats. Although the overall responsiveness towards morphine was not affected by 7 days morphine exposure, a small reduction in the proportion of morphine-induced depressions was observed in chronic morphine-treated rats compared with naive controls. Withdrawn animals did not show this difference. Chronic morphine treatment also increased the frequency of occurrence of naloxone-induced excitation. Pretreatment with PCPA reduced the overall responsiveness of naive animals to morphine but combined with chronic morphine treatment it also increased the proportion of morphine excitations.