Intracerebroventricular Administration Of Morphine Research Articles

The involvement of central beta-endorphin in the cardioprotective effects of remote preconditioning mediated by the intracerebroventricular administration of morphine.

Opioids can mimic the effects of remote cardiac preconditioning and mediate a subsequent reduction in myocardial infarct size. This study investigated the role of beta-endorphin (β-EP) in intracerebroventricular morphine cardioprotection. Anesthetized, open-chest, male Sprague-Dawley rats were assigned to 1 of 9 treatment groups 3days after intracerebroventricular catheter placement. Remote preconditioning was induced with 3μg/kg of morphine. The β-EP antagonist was administered via intracerebroventricular or intravenous routes either 10min before or immediately after morphine or saline administration. Ischemia-reperfusion injury was caused by 30min of left coronary artery occlusion followed by 120min of reperfusion. The infarct size, as a percentage of the area at risk, was determined by 2,3,5-triphenyltetrazolium staining. Radioimmunoassay and immunoreactivity were used to determine the β-EP levels in the serum and brain. Intracerebroventricular administration of β-EP antiserum (AEP) after morphine administration attenuated the cardioprotective effects of remote preconditioning. The addition of intravenous AEP either before or after morphine did not affect infarct size. After morphine preconditioning, the β-EP level decreased in the hypothalamic arcuate nucleus and increased significantly in the serum, pituitary gland, ventrolateral periaqueductal gray and rostral ventrolateral medulla. Central but not peripheral β-EP is involved in morphine remote preconditioning and plays a role in the ongoing mediation of cardioprotective effects.

Deficits in neuronal cytochrome P450 activity attenuate opioid analgesia but not opioid side effects

Morphine-like analgesics act on µ opioid receptors in the CNS to produce highly effective pain relief, but the same class of receptors also mediates non-therapeutic side effects. The analgesic properties of morphine were recently shown to require the activity of a brain neuronal cytochrome P450 epoxygenase, but the significance of this pathway for opioid side effects is unknown. Here we show that brain P450 activity is not required for three of morphine׳s major side effects (respiratory depression, constipation, and locomotor stimulation). Following systemic or intracerebroventricular administration of morphine, transgenic mice with brain neuron – specific reductions in P450 activity showed highly attenuated analgesic responses as compared with wild-type (control) mice. However, brain P450-deficient mice showed normal morphine-induced side effects (respiratory depression, locomotor stimulation, and inhibition of intestinal motility). Pretreatment of control mice with the P450 inhibitor CC12 similarly reduced the analgesia, but not these side effects of morphine. Because activation of brain µ opioid receptors produces both opioid analgesia and opioid side effects, dissociation of the mechanisms for the therapeutic and therapy-limiting effects of opioids has important consequences for the development of analgesics with reduced side effects and/or limited addiction liability.

Are we able to Manage Effectively Opioid-Induced Bowel Dysfunction?

The patomechanism of OIBD comprises both peripheral and central mechanisms. The peripheral opioid effect on µ-opioid receptors in the gut wall plays the main role here [3]. High density of µ-opioid receptors was found in neurons of myenteric and submucosal plexus and immune cells in the lamina propria [4]. Opioid receptors (predominantly µ, also κ and δ) are located in the gut wall in the myenteric plexus and in the submucosal plexus. The former are responsible for GI motility and the latter for secretion. The µ-opioid receptors are activated in the wall of the stomach, small and large intestine by endogenous (enkephalins, endorphins and dynorphins) and exogenous (codeine, dihydrocodeine, hydrocodone, tramadol, morphine, oxycodone, hydromorphone, fentanyl, buprenorphine, methadone) opioids and modify GI function. Activation of µ-opioid receptors inhibits excitatory and inhibitory neural pathways within the enteric nervous system that coordinates motility. Inhibition of excitatory neural pathways depresses peristaltic contractions. The blockade of inhibitory neural pathways increases GI muscle activity, elevates resting muscle tone, spasm and non-propulsive motility patterns. These mechanisms are responsible for delayed gastric emptying and slowing the intestinal transit [5]. The central mechanism of opioid effects on GI tract was demonstrated as intracerebroventricular administration of morphine in rats inhibited gastrointestinal propulsion. This effect was reversed by intracerebroventricular administration of naloxone and vagotomy. Intrathecal administration of morphine reduced gastroduodenal motility and intramuscular morphine gave additional effects. Thus both central and peripheral opioid effects play a role in opioid GI effects [6]. Treatment of Opioid-Induced Bowel Dysfunction General measures comprise the meticulous assessment and applying prophylactic measures matched to patients’ general condition. Change of diet (increased food and fluid intake), more physical activity, sitting position during bowel movement and privacy during defecation process are recommended. Patients treated with opioids should be considered for prokinetic administration (metoclopramide, domperidone, itopryd) [7]. Reversible causes such as hypercalcemia should also be treated. Discontinuing or decreasing doses of drugs that may contribute to constipation development (such as tricyclics, neuroleptics, anticholinergics) should also be considered. Patients and families should be educated about the ways of prevention and treatment of OIBD. In majority of patients with OIBD laxatives need to be administered. The general recommendation is to combine oral administration of osmotic agents (usually lactulose or macrogol) which have an osmotic effect in the colon with stimulants activating neurons in the myenteric and submucosal plexus in colon and reducing absorption of water and electrolytes from the intraluminal contents: anthracenes (senna), polyphenolics (bisacodyl) or sodium picosulphate [8]. However, these drugs display limited efficacy in patients suffering

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Increasing evidence suggests there is a sex difference in opioid analgesia of pain arising from somatic tissue. However, the existence of a sex difference in visceral pain and opioid analgesia is unclear. This was examined in the colorectal distention (CRD) model of visceral pain in the current study. The visceromotor response (vmr) to noxious CRD was recorded in gonadally intact male and female rats. Subcutaneous injection of morphine dose-dependently decreased the vmr in both groups without affecting colonic compliance. However, morphine was significantly more potent in male rats than females. Because systemic morphine can act at peripheral tissue and in the central nervous system (CNS), the source of the sex difference in morphine analgesia was determined. The peripherally restricted mu-opioid receptor (MOR) antagonist naloxone methiodide dose-dependently attenuated the effects of systemic morphine. Systemic administration of the peripherally restricted MOR agonist loperamide confirmed peripherally mediated morphine analgesia and revealed greater potency in males compared with females. Spinal administration of morphine dose-dependently attenuated the vmr, but there was no sex difference. Intracerebroventricular administration of morphine also dose-dependently attenuated the vmr with significantly greater potency in male rats. The present study documents a sex difference in morphine analgesia of visceral pain that is both peripherally and supraspinally mediated.

Morphine and somatostatin analogue reduce c-fos expression in trigeminal subnucleus caudalis produced by corneal stimulation in the rat

The influence of morphine and somatostatin on nociceptor-evoked activation of central trigeminal neurons and cardiovascular reflex responses was assessed in barbiturate-anaesthetized rats. Morphine or the somatostatin analogue, octreotide, was given intracerebroventricularly 20 min prior to application of mustard oil to the corneal surface. The expression of the immediate early gene, c-fos, was used to estimate neuronal activation within the spinal trigeminal nucleus. Morphine reduced the number of Fos-positive neurons produced at the transition region between trigeminal subnucleus caudalis and the upper cervical spinal cord, whereas c-fos expression at the subnucleus interpolaris/caudalis transition was not affected significantly. Morphine also reduced the arterial pressure and heart rate responses to corneal stimulation in proportion to the dose of morphine and required a threshold dose similar to that which reduced c-fos expression. Naloxone prevented the morphine-induced inhibition of c-fos expression and cardiovascular reflex responses to corneal stimulation. Somatostatin analogue reduced the number of Fos-positive neurons at the subnucleus caudalis/cervical cord transition, but not at the subnucleus interpolaris/caudalis transition, an effect that was not prevented by naloxone. Somatostatin analogue did not blunt the cardiovascular responses evoked by corneal stimulation. A subthreshold dose of morphine plus a threshold dose of somatostatin analogue caused a greater inhibition of Fos-positive neurons at the subnucleus caudalis/cervical cord transition, but not in reflex-evoked autonomic responses, than the same dose of either drug alone. Intracerebroventricular administration of morphine and somatostatin analogue inhibit corneal activation of neurons within the superficial laminae at the subnucleus caudalis/cervical cord transition through opioid and non-opioid-dependent neural pathways, respectively. By contrast, the low sensitivity of corneal-responsive neurons at the subnucleus interpolaris/caudalis transition to analgesics suggests that these neurons are not simply a rostral extension of the medullary dorsal horn. Correlation analyses suggest that morphine-induced inhibition of cardiovascular responses to corneal stimulation depend on the activity of neurons at the subnucleus caudalis/cervical cord transition and not on those at the subnucleus interpolaris/caudalis transition region.

Morphine pharmacokinetics and pain assessment after intracerebroventricular administration in patients with terminal cancer

Morphine pharmacokinetics and pain relief were evaluated after intracerebroventricular administration of morphine (0.4 +/- 0.11 mg) in seven patients with cancer suffering from intractable pain. Ventricular cerebrospinal fluid (CSF), lumbar CSF, and plasma morphine concentrations were analyzed by a specific morphine radioimmunoassay. A two-compartment model was sufficient to describe the kinetics of morphine in ventricular CSF. Morphine diffuses to the lumbar level, and the mean maximum concentration was 192 +/- 105 ng/ml at 4.5 +/- 1.3 hours. Ventricular and lumbar CSF morphine kinetics showed a similar decline during the elimination phase, with terminal half-lives of 3.8 +/- 0.6 hours and 4.2 +/- 1.6 hours, respectively. Pain relief was evaluated by a visual analog scale: the test showed a rapid onset of analgesia (less than 10 minutes). Analgesic effectiveness reached a maximum between 6 and 10 hours. The relationship between pharmacologic effect and morphine concentrations in ventricular CSF resulted in an anticlockwise hysteresis curve. The presence of morphine in lumbar CSF suggested an additive spinal action of morphine, which probably plays a role in the duration of analgesia.

Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats

Gender and gonadal function have previously been shown to influence the magnitude of analgesia following systemic morphine and opioid and nonopioid forms of swim analgesia with male rats displaying greater analgesia than female rats and gonadectomy reducing analgesic magnitude in both genders. These effects have been presumed to be centrally mediated. The present study evaluated the roles of gender, gonadectomy and estrous phase upon dose-response and time-response functions of analgesia following intracerebroventricular administration of morphine as measured by the tail-flick and jump tests. Sham-operated male rats displayed significantly greater magnitudes of peak and total analgesia following central morphine than sham-operated female rats on both nociceptive measures. This striking effect was reflected both in terms of magnitude and ED 50; while male rats displayed near-maximal analgesia at a 5 μg dose of morphine, female rats displayed moderate analgesia at doses as high as 40 μg of morphine. Castration produced small, but significant reductions in the magnitude of central morphine analgesia; the ED 50 of morphine analgesia, however, was not changed. Although female rats in either proestrous or estrous displayed significantly greater magnitudes of analgesia than ovariectomized rats or rats in a combined met-/di-estrous phase at some doses, the ED 50 of morphine analgesia was not significantly altered as functions of estrous phase or ovariectomy. The interaction of opiate receptors and gonadal steroid receptors is considered as one possible determinant of gender differences observed in the magnitude and potency of central morphine analgesia.

Lesions to ascending noradrenergic and serotonergic pathways modify antinociception produced by intracerebroventricular administration of morphine

Ascending noradrenergic and serotonergic pathways were lesioned by injection of 6-hydroxydopamine into the dorsal bundle or 5,7-dihydroxytryptamine into the ventromedial tegmentum respectively, and the antinociceptive effect of morphine, administered by intracerebroventricular injection assessed using the tail-flick test 3–14 days later. Lesions of the dorsal bundle selectively depleted levels of noradrenaline (NA) in the forebrain and increased the antinociceptive effect of morphine early, but not later, in the time course of action. Lesions to the locus coerueleus depleted NA in the forebrain and spinal cord but had no effect on the antinociceptive action of morphine. Lesions of the ventromedial tegmentum selectively depleted 5-hydroxytryptamine (5-HT) in the forebrain and transiently reduced the action of morphine. 5,7-Dihydroxytryptamine given intraventricularly depleted 5-HT in the forebrain and spinal cord and also transiently reduced the antinociceptive effect of morphine. These results indicate that aminergic pathways, projecting to the forebrain, are involved in the suppression of the tail-flick reflex produced by injection of morphine into the lateral ventricle.

Luteinizing hormone secretion following intracerebroventricular administration of morphine in the prepuberal gilt

Antagonism of endogenous opioids with naloxone stimulates luteinizing hormone (LH) release in mature but not prepuberal gilts. The present report demonstrates that the opiate agonist morphine (500 μg), administered intracerebroventricularly (ICV), reduced LH secretion in both ovariectomized mature and prepuberal gilts. We suggest that opioid receptors are functionally coupled to the GnRH secretory system in prepuberal gilts even though endogenous opioid peptide modulation of LH secretion was not demonstrable in our previous studies.

μ-, but not δ-, opioid receptor-mediated antinociception in mice is attenuated by γ-irradiation

Mice were exposed to whole-body irradiation (500 rads) from a 137Cs γ-source and tested 2 h later for antinociception (tail-flick test) produced by intracerebroventricular administration of morphine or the more δ-selective opioid peptide, [ d-Pen 2, l-Pen 5]enkephalin (DPLPE). Irradiation significantly attenuated the antinociception produced by morphine, but not by DPLPE. These results demonstrate a differential sensitivity of μ- and δ-opioid receptors to γ-irradiation and, in addition, may be of clinical relevance for cancer patients receiving concurrent radiation therapy and opioid analgesics.

Effects of Morphine on Gastric Ulceration, Barrier Mucus and Acid Secretion in Pylorus-Ligated Rats

The effects of intraperitoneal (IP) or intracerebroventricular (ICV) administration of morphine on acid and pepsin secretion, gastric ulceration and gastric bound mucoproteins were investigated in pylorus-ligated rats. Morphine, administered IP, produced a dose-dependent inhibition of the gastric secretion volume, acidity, pepsin output and bound mucoproteins. By contrast, the effect of morphine on gastric ulcers was not dose-dependent: a significant increase in gastric lesions was obtained with morphine 5 mg/kg IP. Naloxone IP prevented the effects of morphine on gastric secretory volume, acidity and pepsin output, but not on gastric mucus and ulcer score. ICV administration of morphine induced a dose-dependent inhibition of secretory volume, acidity and ulcer score, whereas no modification of gastric mucus was observed. Naloxone ICV prevented the effects of ICV morphine. Overall results suggest that morphine inhibits gastric secretion through both central and peripheral opioid receptors, whereas the inhibitory effect of morphine on bound mucus appears to be exerted on mucus synthesis through peripheral opioid receptors. This inhibitory effect on barrier mucus accounts at least in part for the gastric ulcerogenic action of morphine.

Analgesic cross-tolerance between morphine and opioid peptides.

The analgesic effect of intracerebroventricular administration of morphine, ketocyclazocine, [D-ala2]-methionine enkephalinamide (DAM), [D-ala2-D-leu5]-enkephalin (DADLE), leuenkephalin, metenkephalin, and beta-endorphin on acetic acid-induced abdominal writhing (AAW) was investigated in naive and morphine-tolerant mice. It was found that the relative potencies of a series of opioids are different in naive and morphine-tolerant groups. In naive animals, the order of potency (ED50, nmol) was beta-endorphin greater than morphine = DAM greater than DADLE greater than ketocyclazocine = leuenkephalin = metenkephalin. The morphine-tolerant animals were cross-tolerant to ketocyclazocine and to all the peptides studied; DAM and beta-endorphin exhibited the highest degree of tolerance. In morphine-tolerant animals, the order of potency was morphine = DADLE = beta-endorphin greater than DAM = ketocyclazocine = metenkephalin greater than leuenkephalin. The results indicate that endogenous opioid systems may be affected by tolerance development to morphine.

Effect of narcotic analgesics on plasma cyclic AMP levels in male mice

Systemic administration of morphine, as well as pethidine and pentazocine, increased plasma cyclic AMP levels in male mice. Intracerebroventricular administration of morphine and β-endorphin also increased plasma cyclic AMP levels. The effect of morphine and β-endorphin was antagonized by naloxone indicating the involvement of opiate receptors in the central nervous system for the effect of morphine on cyclic AMP levels. Tolerance was shown to develop to the action of morphine in increasing the plasma cyclic AMP. The morphine-induced increase in plasma cyclic AMP was abolished by treatment with propranolol or pentolinium or by adrenalectomy but not by treatment with atropine, phentolamine, 6-hydroxydopamine or α-methyltyrosine. These findings suggest that morphine increases plasma cyclic AMP levels mainly by releasing catecholamines, from the adrenal medulla, and these activate adenylate cyclase via the stimulation of β-adrenoceptors.

275) - Changes in urine outflow with Intracerebroventricular administration of morphine and its related compounds in rats

275) - Changes in urine outflow with Intracerebroventricular administration of morphine and its related compounds in rats

Rumination in sheep: Effects of morphine, deslanoside and ablation of area postrema

Abstract Continuous long-term recording of masticatory movements was obtained in four sheep housed in individual stalls. Total rumination time occupied about 33 per cent, and feeding activity an additional 25 per cent of the whole day. Intravenous injection of morphine sulfate, 1.0 mg/kg, did not produce a significant alteration in feeding or rumination behavior. By contrast, intracerebroventricular administration of morphine, 0.4 to 2.0 mg total, elicited compulsive and uninterrupted chewing activity for up to 15 hr. Apomorphine produced an effect similar to that of morphine, but of short duration. Intravenous injection of deslanoside, 0.04–0.08 mg/kg, resulted in complete inhibition of rumination for as long as 18 hr with little or no reduction in feeding activity. Forestomach (reticular) movements were also inhibited by the deslanoside. Vomiting was not elicited by any form of drug treatment. Chronic ablation of area postrema in the lower brain stem did not notably influence the character of spontaneous feeding and rumination behavior; it did not modify the compulsive chewing response to morphine; it abolished the inhibition of rumination as well as of reticular movements caused by deslanoside.