naloxone and Pheochromocytoma

Topics: Adrenal Gland Neoplasms; Animals; Cardiovascular Physiological Phenomena; Endorphins; Humans; Naloxone; Pheochromocytoma; Receptors, Opioid; Shock

To evaluate whether opioid receptor blockade might modulate sympathetic-adrenal activity, we studied the effects of placebo or naloxone administration on plasma catecholamine (CA) levels in a group of 13 normal subjects and 15 hypertensive patients suspected to have a pheochromocytoma. Diagnostic evaluation confirmed the presence of pheochromocytoma in 9 patients. Among these, 4 had a unilateral epinephrine (E)-secreting tumor, 3 had bilateral E-secreting tumors due to multiple endocrine adenomatosis type IIa, and 2 had a unilateral norepinephrine (NE)-secreting tumor. In each subject studied, CA secretion was evaluated by calculating the area (0-30 min) under the plasma hormone curves after placebo or naloxone administration. In normal subjects naloxone caused a significant increase (P less than 0.005) of E secretion, whereas NE did not change. Similarly, in the group of hypertensive patients, E secretion increased after naloxone (P less than 0.01). In pheochromocytoma patients naloxone caused a significant increase in E (P less than 0.05) and NE (P less than 0.01) secretion from E-producing tumors but no increase in the patients with NE-secreting pheochromocytomas. The study suggests that CA secretion from normal and pathological chromaffin tissue is modulated by endogenous opioids; this modulation seems particularly evident in patients with E-secreting pheochromocytoma.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Aged; Catecholamines; Chromaffin System; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Pheochromocytoma; Receptors, Opioid

Human pheochromocytoma cells, which are demonstrated to contain and release met-enkephalin and norepinephrine, may be a promising resource for cell therapy in cancer-induced intractable pain. Intrathecal injection of alginate-poly (l) lysine-alginate (APA) microencapsulated human pheochromocytoma cells leads to antinociceptive effect in a rat model of bone cancer pain, and this effect was blocked by opioid antagonist naloxone and alpha 2-adrenergic antagonist rauwolscine. Neurochemical changes of cerebrospinal fluid are in accordance with the analgesic responses. Taken together, these data support that human pheochromocytoma cell implant-induced antinociception was mediated by met-enkephalin and norepinephrine secreted from the cell implants and acting at spinal receptors. Spinal implantation of microencapsulated human pheochromocytoma cells may provide an alternative approach for the therapy of chronic intractable pain.

Topics: Adrenal Gland Neoplasms; Alginates; Animals; Biocompatible Materials; Bone Neoplasms; Cell Transplantation; Enkephalins; Female; Humans; Naloxone; Nociceptive Pain; Norepinephrine; Pheochromocytoma; Polylysine; Rats; Rats, Sprague-Dawley; Spinal Cord; Yohimbine

Pheochromocytomas are catecholamine-secreting tumors that also synthesize and secrete several neuropeptides, including opioids. A negative regulation of catecholamine secretion by opioids has been postulated in chromaffin cells. However, results obtained so far are contradictory when referred to human pheochromocytomas. The aim of this study was to define the role of locally produced enkephalins on catecholamine release in human pheochromocytoma cells.. Cells obtained from eleven human pheochromocytomas of different genetic origins were cultured for 5 days. Cultures were maintained under basal condition or under enkephalin, dexamethasone and naloxone alone or in combination with enkephalin or dexamethasone-stimulated conditions. Catecholamine and enkephalin levels in the culture medium were measured by HPLC-ED and RIA respectively.. Enkephalin induced a decrease in norepinephrine levels in all tumor cultures. Dexamethasone treatment, which increased enkephalin levels, also decreased catecholamine levels. On the other hand, the addition of naloxone to the cultures reverted to normal the inhibitory action exerted by enkephalin and dexamethasone treatments.. These results suggest the existence of an autocrine negative regulatory loop exerted by enkephalin on norepinephrine release in human pheochromocytoma cells.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Anti-Inflammatory Agents; Autocrine Communication; Catecholamines; Cell Separation; Cell Survival; Cells, Cultured; Child; Culture Media; Dexamethasone; Enkephalin, Methionine; Enkephalins; Female; Humans; Indicators and Reagents; Male; Middle Aged; Naloxone; Narcotic Antagonists; Pheochromocytoma

We have examined how fentanyl modulates [3H]noradrenaline uptake in two cultured neuronal cell preparations, the human neuroblastoma SH-SY5Y and the rat phaeochromocytoma PC12. Fentanyl produced a significant, dose-dependent inhibition of [3H]noradrenaline uptake at concentrations in excess of 0.1 mumol litre-1 (P < 0.05) and 0.3 mumol litre-1 (P < 0.05) for PC12 and SH-SY5Y cells, respectively. However, these values exceed the serum concentration of fentanyl required to produce analgesia. At the maximum concentration examined (100 mumol litre-1), fentanyl produced 85-95% inhibition of uptake. This effect was not antagonized by naloxone, implying a nonopioid mechanism of action. Imipramine 1 mumol litre-1 reduced [3H]noradrenaline uptake by 65-70% but morphine, in contrast to fentanyl, had no effect (P > 0.1).

Topics: Adrenal Gland Neoplasms; Animals; Dose-Response Relationship, Drug; Fentanyl; Humans; Imipramine; Morphine; Naloxone; Neuroblastoma; Neurons; Norepinephrine; Pheochromocytoma; Rats; Time Factors; Tumor Cells, Cultured

The present study investigated whether in vivo endogenous opioids inhibit the secretory activity of pheochromocytomas and whether opioid antagonists may be useful in the diagnosis of pheochromocytoma. In six patients with pheochromocytoma in whom the diagnosis was histologically confirmed after surgery, mean intraarterial blood pressure (BP) increased by 45 mm Hg within 3 min after intravenous (i.v.) injection of 2 mg glucagon (95% confidence interval 23-68 mm Hg); heart rate (HR) remained unchanged, whereas plasma norepinephrine (NE) increased by 216% (31-658%) and plasma epinephrine (EPI) increased by 203% (37-571%). Although glucagon stimulation confirmed the secretory potential of the pheochromocytomas, opioid antagonism by a 10-mg i.v. bolus of naloxone produced no significant change in plasma NE and EPI concentrations or intraarterial pressure. The present study does not support the hypothesis that release of catecholamines from pheochromocytomas is inhibited by endogenous opioids. Use of opioid antagonists as a tool in the diagnosis of pheochromocytoma therefore cannot be recommended.

Topics: Adrenal Gland Neoplasms; Adult; Blood Pressure; Catecholamines; Cold Temperature; Epinephrine; Female; Glucagon; Heart Rate; Hemodynamics; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Norepinephrine; Pheochromocytoma

Recent investigations have shown that the widely used clonidine suppression test is sometimes fallible for the diagnosis of pheochromocytoma. A comparative assessment was made of the following suppression and provocation tests, the clonidine suppression test, and the glucagon, metoclopramide, and naloxone provocation tests. The assessment was performed in 6 patients with pheochromocytoma and in 19 patients without pheochromocytoma who were initially suspected of harboring a tumor. BP response did not predict the presence of pheochromocytoma in any test. Plasma norepinephrine (NE) concentrations determined at 120 and 180 min after oral 150 micrograms of clonidine gave false negative results in 2 of the 5 patients with pheochromocytoma tested. Both plasma NE and epinephrine (E) concentrations were measured before and sequentially after each provocative agent. Neither NE nor E responded to 1 mg of glucagon iv in 2 of the 4 patients with pheochromocytoma tested. Determination of the peak level, peak increment, and % peak increment of NE and E following 10 mg of naloxone iv did not distinguish the two groups. The % peak increments of both NE and E in all 4 patients with pheochromocytoma given 5 mg of metoclopramide iv exceeded the mean + 3 SD values of the patients without pheochromocytoma (25 + 28% for NE, and 25 + 42% for E). These results suggested that, when performed with judicious patient selection (ambiguous plasma or urinary catecholamine levels), the measurement of plasma catecholamines in response to metoclopramide can be a useful adjunctive tool in the diagnosis of pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Blood Pressure; Clonidine; Epinephrine; Female; Glucagon; Humans; Kinetics; Male; Metoclopramide; Middle Aged; Naloxone; Norepinephrine; Pheochromocytoma

Hypertension due to pheochromocytoma is generally considered to be a straightforward, direct consequence of the elevated concentrations of circulating catecholamines. However, clonidine, a centrally acting antihypertensive drug, has been reported to lower blood pressure in patients with pheochromocytoma, suggesting the possibility that the sympathetic nervous system is involved in the maintenance of hypertension in this disease. We have investigated this possibility in New England Deaconess Hospital rats harboring a transplantable pheochromocytoma that secretes norepinephrine and dopamine. Both clonidine and chlorisondamine, a ganglionic blocker, markedly decreased blood pressure in tumor-bearing rats. However, in other rats made acutely hypertensive with a norepinephrine infusion, neither clonidine nor chlorisondamine decreased blood pressure. This result indicates that in an acute model of hypertension, where baroreflex mechanisms have likely withdrawn sympathetic tone, neither clonidine nor chlorisondamine had nonspecific antihypertensive effects. A central nervous system site of action for the antihypertensive effect of clonidine in the rats harboring pheochromocytoma was suggested by the observation that the opiate antagonist naloxone both reversed and prevented clonidine's effect on blood pressure. Prazosin and yohimbine were utilized to determine the respective contributions of alpha-1 and alpha-2 adrenergic receptors in the maintenance of hypertension in rats harboring pheochromocytoma. Both drugs markedly lowered blood pressure in these rats. Our data suggest that both the sympathetic nervous system and circulating catecholamines are involved in the maintenance of hypertension due to pheochromocytoma.

Topics: Adrenal Gland Neoplasms; Animals; Chlorisondamine; Clonidine; Hypertension; Naloxone; Pheochromocytoma; Rats; Sympathetic Nervous System

The effects of low- (2 mg) and high-dose (10 mg) intravenous naloxone administration on circulating plasma catecholamines in four patients with proven and two patients with suspected phaeochromocytomas have been evaluated. In three out of four patients with confirmed phaeochromocytomas or paragangliomas, 10 mg naloxone resulted in a marked rise (290-575%) in circulating noradrenaline; despite combined alpha and beta-adrenoceptor blockade, in two out of four cases systolic and diastolic pressures rose whilst pulse rate fell. No response was seen to 2 mg naloxone in any patient. No humoral or pressor response was obtained in the fourth patient, who may have been secreting maximal levels of plasma noradrenaline at the time of study. In the two patients with suspected phaeochromocytoma, there was no response to naloxone: further investigations failed to reveal a source of abnormal catecholamine secretion in these patients. It is concluded that naloxone represents a new pharmacological agent which can provoke catecholamine release in patients with phaeochromocytomas; in such patients, endogenous opioids may regulate catecholamine release either from the tumour itself or from the enhanced peripheral catecholamine stores.

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Blood Pressure; Catecholamines; Female; Humans; Male; Middle Aged; Naloxone; Paraganglioma; Pheochromocytoma; Pulse

The tissue contents of catecholamines (CAs) and methionine-enkephalin-like immunoreactivity (Met-enk) were examined in 8 patients with phaeochromocytomas (Phs). In 6, Ph cells were cultured, and the modes of secretion of CAs and Met-enk were examined. Tissue contents of CAs and Met-enk varied from patient to patient, but larger amounts of Met-enk were found in medullary Phs than extramedullary ones, regardless of the secreting CA type. Three patients with extramedullary Phs had clinically showed a sustained hypertension, whereas five with medullary Phs were normotensive or had occasional paroxysmal hypertension. Nicotine (10(-7) M to 10(-4) M) stimulated simultaneous secretion of CAs and Met-enk from the cultured human Ph cells. Met-enk, however, was not secreted in proportion to either epinephrine (E), norepinephrine (NE) or total CAs (E + NE). Met-enk, FK33-824 (FK) (Met-enkephalin analogue), and dynorphin 1-13 (Dyn) significantly suppressed the secretion of CA evoked by 10(-5) M nicotine. The 50% inhibitory concentrations (IC50) of Met-enk, FK, and Dyn were 5 X 10(-6) M, 9.9 X 10(-5) M, and 9.0 X 10(-8) M, respectively, in one patient and 9.0 X 10(-6) M, 1.5 X 10(-7) M, and 1.4 X 10(-7) M in another. In one patient, 10(-5) M naloxone inhibited the CA secretion evoked by 10(-5) M nicotine and did not reverse the 10(-5) M FK-induced suppression of CA secretion in the presence of 10(-5) M nicotine. These results suggest that human Phs may be heterogeneous with regard to storage and secretion of CAs and opioid peptides.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adrenal Gland Neoplasms; Adult; Cells, Cultured; D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; Endorphins; Enkephalin, Methionine; Epinephrine; Female; Humans; Hypertension; Male; Middle Aged; Naloxone; Nicotine; Norepinephrine; Pheochromocytoma

Topics: Adrenal Gland Neoplasms; Adult; Catecholamines; Humans; Male; Naloxone; Pheochromocytoma; Receptors, Opioid

Specific enkephalin binding was found in a rat pheochromocytoma cell line, PC12 (subclone h), when cultured in the presence of nerve growth factor (NGF; 50 ng/ml). Specific binding of [3H][D-Ala2]Met-enkephalinamide was saturable with a KD=2.4 nM and Bmax = 866 fmol/mg of protein. The binding was displaced completely by morphine and naloxone at a concentration of 10(-4) and 10(-6) M, respectively. beta-Endorphin and dynorphin [1-13] also displaced the binding; KI = 9.6 and 81.6 nM, respectively. Enkephalin binding in PC12h cells cultured in the absence of NGF was very low. Binding was dramatically increased when cultured in the presence of NGF for 7 to 10 days. The enkephalin binding was induced by NGF in the cells cultured in a hormone-supplemented serum-free medium. In contrast, epidermal growth factor was of two orders lower potency, and insulin had no effect on the expression of enkephalin binding sites. Since the differentiation effects of NGF on PC12h cells are though to offer a model system to investigate the effect of NGH on neurons, the present observations may suggest a physiological role for NGF in the induction and maintenance of specific opiate receptors during development of the autonomic nervous system.

Topics: Animals; beta-Endorphin; Cell Line; Endorphins; Enkephalin, Methionine; Enkephalins; Kinetics; Morphine; Naloxone; Nerve Growth Factors; Pheochromocytoma; Rats; Receptors, Opioid