Role Of Endogenous Opioid System Research Articles

Assessment of endogenous opioid mediation in stress-induced hypercholesterolemia in the rat.

Stressful stimuli are known to elevate total plasma cholesterol levels and activate endogenous opioid systems. In cholesterol-cholic, acid-fed female rats, a 5-day unpredictable immobilization stress paradigm increased levels of low plus very low density lipoprotein cholesterol and reduced levels of high density lipoprotein cholesterol. Pretreatment with the opiate antagonist, naltrexone (1.0 mg/kg, sc) prevented the stress-induced changes. Five-day morphine pellet implants (75 mg) duplicated the cholesterol alterations seen in immobilized rats. In addition, plasma triglyceride levels were elevated in morphine pelleted rats, but hepatic and aortic cholesterol levels were unchanged. Unchanged plasma sorbitol dehydrogenase activity and hepatic triglyceride levels indicated that both regimens were not hepatotoxic. These findings support the possible role for endogenous opioid systems in stress-induced hypercholesterolemia.

Modulation of human neuroblastoma transplanted into nude mice by endogenous opioid systems

The role of endogenous opioid systems (endogenous opioids and opioid receptors) in human cancer was explored using an opioid antagonist paradigm and neuroblastoma cells (SK-N-MC) transplanted into nude mice. Mice inoculated with 2.5 × 106 neuroblastoma cells received daily injections of either 0.1 or 10 mg/kg naltrexone (=0.1 and 10 NTX groups) which blocked the opioid receptor for 6–8 hr/day or the entire 24 hr/day, respectively, or sterile water. The latency for appearance of a measurable tumor (5 mm diameter) in the 0.1 NTX group was 27% longer than controls (11 days), and the first death in this group occurred 33% later than controls (day 27). Mice inoculated with tumor cells in the 10 NTX group had an acceleration (18%) in the latency of tumor appearance and, 2 weeks after cell inoculation, 70% of the mice in this group had tumors, in contrast to 10% of the controls. At the termination of the experiment (day 45), only 33% of the 10 NTX group were alive, in contrast to 90% of the controls. Receptor binding assays using DAGO, DADLE, or EKC revealed specific saturable binding only for DADLE and EKC. NTX administration resulted in a 148–186% increase in density for both binding sites, but no changes in binding affinity. Measures of opioid levels showed that tumor tissue levels of both β-endorphin and methionine-enkephalin were elevated 2.5 to 6.5 fold from control values in both NTX groups, whereas plasma β-endorphin was subnormal by 4 to 6 fold. These results indicate that endogenous opioid systems regulate human neurooncogenesis, with opioids being active inhibitors of growth. Opioid antagonists up-regulate receptors and increase tissue levels of endogenous opioids and, under conditions in which the opioid antagonist is short-acting (e.g., 0.1 NTX), can have an exaggerated antitumor effect during the interval when the antagonist is no longer present.

Endogenous opioid systems regulate cell proliferation in the developing rat brain

The role of endogenous opioid systems in modulating the proliferation of developing cerebellar cells was examined autoradiographically in 6-day-old rats. The blockade of endogenous opioid-opioid receptor interaction by naltrexone, a potent opioid antagonist, was accompanied within 1–2 h by an increased proportion of cells incorporating [ 3H]thymidine. When high doses of naltrexone (50 mg/kg) were administered this index was still elevated 12 h later; however, when low doses of naltrexone (1 mg/kg) were administered the index of labeled cells was decreased markedly. Injection of methionine-enkephalin, an endogenous opioid peptide, also resulted in a decrease in the proportion of cells incorporating [ 3H]thymidine. Concomitant injection of 1 mg/kg naloxone, however, blocked the inhibitory effects of methionine-enkephalin on cell division but did not itself affect cell generation. These studies demonstrate that endogenous opioid systems can regulate the proliferation of cell populations in the developing nervous system and do so through an inhibitory mechanism.

Opioid antagonist-induced modulation of cerebral and hippocampal development: histological and morphometric studies.

The role of endogenous opioid systems in preweaning cerebral and hippocampal development was explored in rats utilizing naltrexone, a potent opioid antagonist. Sprague-Dawley rats were given daily injections (s.c.) of either 1 or 50 mg/kg naltrexone to invoke a temporary or complete blockade, respectively, of opioid receptors throughout the first 3 weeks of postnatal life; animals injected with sterile water served as controls. At weaning (Day 21), macroscopic, morphometric, and histological assessments were undertaken. In general, 50 mg/kg naltrexone had a stimulatory action on brain development, whereas 1 mg/kg naltrexone had an inhibitory influence. In most cases, both males and females were affected comparably. Opioid antagonist action was especially directed at cellular and tissue differentiation, with marked changes in macroscopic and areal dimensions and histotypic organization observed in the cerebrum. A prominent effect on the cerebrum of the 1 mg/kg naltrexone group was a substantial increase in packing density of the neural cells, reflecting a reduced area for accommodating neural elements. Changes in the hippocampus were largely restricted to the 1 mg/kg group. However, the number of granule cells was increased in the dentate gyrus of the 50 mg/kg group, suggesting that opioid receptor blockade affects cell types undergoing postnatal proliferation. Cellular elements derived prior to naltrexone treatment (e.g., pyramidal neurons) were capable of being influenced in only differentiative capacity. Our results show that endogenous opioids are natural trophic factors in brain development and provide evidence for the crucial role of endogenous opioid-opioid receptor interaction in neuro-ontogeny.

Electroconvulsive shock activates endogenous opioid systems: behavioral and biochemical correlates.

From the evidence reviewed above, there is little doubt that ECS activates endogenous opioids and modifies their receptors. Thus, this form of SIA is accompanied by many other corollaries of opioid-like actions, including catalepsy, similar EEG patterns, common autonomic effects, and increases in opioid receptor binding sites. Investigations have further indicated that the amnestic effects of ECS can also be attenuated by naloxone, and that pituitary-derived opioids may play an important role as a predominant source of opioids that contribute to these opioid-like effects following ECS. It is hoped that these many attempts to correlate SIA with other behavioral and physiological endpoints following ECS will provide a more global perspective on the role of endogenous opioid systems in ECS. From these results, it is suggested that other forms of SIA may also share many of these properties in common with ECS-induced SIA. Nonetheless, ECS and other forms of SIA, such as cold water exposure and restraint, share with ECS a common history of clinical use in the treatment of human depression. It is possible that the common thread linking these experimental observations to endogenous opioid systems may provide new insights into the cause and treatment of mental disorders as well as the perception of pain.

Opioid antagonist (naltrexone) modulation of cerebellar development: histological and morphometric studies

The role of endogenous opioid systems in preweaning cerebellar development was explored in rats utilizing naltrexone, a potent opioid antagonist. Sprague-Dawley rats were given daily subcutaneous injections of either 1 or 50 mg/kg naltrexone to invoke a temporary or complete blockade, respectively, of opioid receptors throughout the first 3 weeks of postnatal life; animals injected with sterile water served as controls. At weaning (day 21), macroscopic, morphometric, and histological determinations were conducted. In general, 50 mg/kg naltrexone had a stimulatory action on cerebellar development, whereas 1 mg/kg naltrexone had an inhibitory influence. Both sexes were affected comparably. Limits to naltrexone's ability to modulate cerebellar ontogeny were noted, with more latitude existing toward growth enhancement than impairment. The temporal course of ontogeny was generally unaltered in naltrexone-treated rats. Rather, only events that transpired over this period were dramatically affected. The most notable effects in 1 mg/kg naltrexone rats were marked decreases in cerebellar areal dimensions, the content of internal granule neurons, and cellular and tissue differentiation. Characteristics of the 50 mg/kg naltrexone group included increases in cerebellar areal dimensions, neural cell number, content, and size, and structural changes consistent with acceleration in growth and differentiation. Naltrexone influenced both neurons and glia, but only neural cells still being generated during the first 21 d after birth were altered in regard to quantity. Previous evidence has shown the presence of peak levels of endogenous opioids and opioid receptors in the cerebellum during the first weeks of life, as well as demonstrating the presence of enkephalin immunoreactivity on germinative cerebellar cells during postnatal neurogenesis but not in adult counterparts.(ABSTRACT TRUNCATED AT 250 WORDS)

Opiate antagonist-induced regulation of organ development

Naltrexone, a potent opioid antagonist, was given to preweaning rats in order to explore the influence of endogenous opioid systems on organogenesis. Sprague-Dawley rats were injected (SC) daily with either 1 or 50 mg/kg naltrexone to invoke a temporary or complete blockade, respectively, of opioid receptors; animals injected with sterile water served as controls. At weaning (Day 21), wet and dry weights, relative organ weight, and tissue water content were determined in 10 organ systems. Naltrexone's effects on growth depended on dosage, sex, and the organ system examined. In general, dosages of 1 and 50 mg/kg naltrexone caused significant decreases and increases, respectively, in organ weight. These changes in wet weight were not due to the state of hydration, but rather to dry weight, indicating that the content of cellular matter was altered. The changes in wet weight were similar to those for body weight, suggesting that a proportional increase or decrease in animal growth took place. Although the same organs in males and females within a dosage group were influenced by naltrexone, and usually to a similar degree, a dosage of 1 mg/kg naltrexone often affected different organ systems than the 50 mg/kg dosage. These results serve as the foundation for subsequent investigations directed towards delineating the role of endogenous opioid systems in developmental biology.

Naltrexone modulates body and brain development in rats: A role for endogenous opioid systems in growth

Preweaning rats receiving daily injections of 20, 50, or 100 mg/kg naltrexone, a potent opiate antagonist, has body and brain weights that were increased 16–22% and 6–13%, respectively, from control levels on day 21 (weaning). All of these dosages of naltrexone blocked the opiate receptor for 24 hr/day as measured in opiate challenge experiments. Dosages of 0.1, 1, and 10 mg/kg naltrexone, which blocked the opiate receptor for less than 12 hr/day, inhibited growth. Repetitive administration of low dosages (3 mg/kg naltrexone, 3 times daily), which blocked the receptor 24 hr/day, increased body and brain development by 31% and 10%, respectively, whereas a cumulative dosage of 9 mg/kg naltrexone given once daily retarded growth. These results show that developmental events are dictated by the duration of opiate receptor blockade and provide compelling evidence that endogenous opioid systems play a crucial role in growth.

Duration of opiate receptor blockade determines tumorigenic response in mice with neuroblastoma: A role for endogenous opioid systems in cancer

The relationship between the pharmacological properties of an opioid antagonist, naltrexone (NTX), and tumor response was studied in mice with transplanted neuroblastoma (NB). Animals receiving 0.1 mg/kg NTX every 6 hr, which blocked morphine-induced analgesia for 24 hr each day, had a 100% tumor incidence, no deviation in time before tumor appearance, and a 17% decrease from control values in total survival time. In contrast, once daily injections of either 0.1 mg/kg NTX or 0.4 mg/kg NTX (the equivalent of 0.1 mg/kg given 4 times daily), which blocked morphine-induced analgesia for less than 10 hr each day, resulted in a tumor incidence of 20% and 60%, respectively, delays in time prior to tumor appearance of 90% and 65%, respectively, and an increased total survival time of 10% and 24%, respectively, for tumor-bearing mice relative to control levels. Inoculation of NB in control animals resulted in 100% tumor appearance within 16 days and a mean survival time of 36 days. These results show that tumorigenic events are dictated by the duration of opiate receptor blockade rather than the dosage of opiate antagonist, and provide compelling evidence that endogenous opioid systems play a crucial role in neuro-oncogenic expression.

Possible interaction between central cholinergic muscarinic and opioid peptidergic systems during memory consolidation in mice

Naloxone (0.01-1.00 mg/kg, ip) facilitated retention of a one-trial inhibitory avoidance task, when administered to male Rockland mice immediately after training, as indicated by performance on a retention test 48 hr later. The dose-response curve was an inverted U in this range of dose. In these conditions naloxone did not lengthen latencies to step-through during the retest of unshocked mice. Higher doses of naloxone (3.00 and 10.00 mg/kg, ip) tended to increase latencies to step-through of both shocked and unshocked mice. These facts rule out an aversive effect of naloxone for low and moderate doses but not for high doses. The influence of naloxone (0.10 mg/kg, ip) on retention was time dependent, which suggests that naloxone facilitated memory consolidation processes. The effects of naloxone were prevented by morphine in both an amnesic and a nonamnesic dose (1.0 and 0.5 mg/kg, ip, respectively). Therefore, naloxone probably facilitated retention as a function of its opiate antagonist properties. The memory facilitation induced by naloxone (0.10 mg/kg, ip) was antagonized by atropine (0.5 mg/kg, ip) but not by methylatropine (0.5 mg/kg, ip), mecamilamine (5 mg/kg, ip), or hexametonium (5 mg/kg, ip). Further, there was a mutual potentiation for both naloxone (0.01 mg/kg, ip) and the muscarinic agonist oxotremorine (6.25 and 12.5 micrograms/kg, ip) administered simultaneously, in doses which had no effect on their own. Moreover, an amnesic dose of atropine (10.00 mg/kg, ip) prevented the enhancement of retention induced by naloxone, while an amnesic dose of morphine (1.00 mg/kg, ip) did not modify the facilitatory effect of oxotremorine (50 micrograms/kg, ip) on retention. An inhibitory modulatory role for endogenous opioid systems on the activity of central cholinergic muscarinic systems during memory consolidation is suggested.

The Role of Endogenous Opioid Systems in Neuroendocrine Regulation

This is a comprehensive review of the opioid agonist and antagonist effects on neuroendocrine function, and the possible neurochemical mechanisms and anatomic loci by which endogenous opioid pepHdes may exert the neuroendocrine modulatory effects. Alsu covered: effects of circulating hormones on hypothalamic pituitary endogenous opioid activity, neurochemical regulation of hypothalamic pituitary endogenous opioid activity, and possible dysfunctions of these systems in depression and implications for the pathophysiology of affective disorders.

Opioid modulation of ingestive behavior

Supportive evidence for an important role of endogenous opioid systems in modulation of ingestive behaviors is presented. Low doses of morphine (1.0–5.0 mg/kg) increase and low doses of naloxone (0.5–2.5 mg/kg) decrease food and water intake during both acute and chronic testing in mildly-deprived rats. Chronic infusions of naloxone with implanted osmotic mini-pumps elicied sustained dose-related suppression of food, water, and saccharin solution intakes but did not reduce ingestion of 10.0% glucose solution or food following 12 hr deprivation. Finally, naloxone treatment did not antagonize nocturnal ingestion of food any more than it reduced day time feeding when the latter was enhanced by prior food deprivation. These results indicate that an opiate agonist and an opiate antagonist modify ingestive behaviors oppositely, affirming that endogenous opioid systems may be involved in control of feeding and drinking. However, their role may be restricted to only indirect participation in homeostatic regulation via neural systems modulating emotional tone or goal-directed behaviors in general.