Evidence for two separate opiate peptide neuronal systems

Watson, Stanley J.; Akil, Huda; Richard, Charles W.; Barchas, Jack D.

doi:10.1038/275226a0

Cited by 409 publications

(75 citation statements)

References 21 publications

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“…These observations are consistent with our hypothesis that the ablation of AgRP neurons removes the inhibitory tone onto postsynaptic cells, resulting in excessive activation by unopposed excitatory inputs. A relatively complete profile of AgRP-and POMCimmunoreactive fibers projected from the ARC has been characterized in rodents (27)(28)(29)(30)(31). However, the functional significance of the overlap in POMC-and AgRP-positive fibers in target areas is not established.…”

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

“…However, the critical signaling molecules that they make and the neural networks that they regulate are unknown. Excessive activation of the melanocortin pathway after ablation of AgRP neurons represents an attractive explanation for the starvation phenotype because AgRP neurons normally inhibit nearby POMC neurons and project to nearly all of the same brain regions as POMC neurons where GABA, NPY, and/or AgRP would individually or in combination counteract melanocortin signaling (1,(26)(27)(28)(29)(30)(31).Feeding behavior can be subdivided into at least two phases: an appetitive phase, characterized by food-seeking behavior that involves motivation to initiate feeding, followed by a consummatory phase that includes ingestion, chewing, and swallowing the food. The appetitive phase involves many brain regions, including the dopaminergic reward pathways (32), whereas the consummatory phase involves the hindbrain that can function independently of forebrain structures (33).…”

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Starvation after AgRP neuron ablation is independent of melanocortin signaling

Howell

Cowley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize ␥-aminobutyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A y /a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A y /a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.T he melanocortin signaling pathway in the medial hypothalamus has emerged as a critical mediator of hormonal and neuronal signals that regulate energy balance (1-3). Genetic, pharmacological, anatomical, and electrophysiological techniques have established a pivotal role for proopiomelanocortin (POMC) neurons in the arcuate (ARC) and their signaling via melanocortin (␣-MSH) to cells bearing melanocortin-4 receptors (MC4R) in the paraventricular nucleus (PVN) and other brain regions in the control of appetite and metabolism (1,4,5). Neighboring cells that coexpress neuropeptide Y (NPY) and agouti-related protein (AgRP) also have been implicated in appetite and energy balance because these peptides stimulate robust feeding when injected into the brain, and their mRNA levels increase in the ARC under starvation conditions, as well as in obese animals deficient in leptin signaling (2,(6)(7)(8). Various experiments suggest that NPY acts by inhibiting the activity of POMC neurons and postsynaptic MC4R-bearing cells by activating G␣i-coupled NPY Y1 and/or Y5 receptors (7, 9-12). The activation of these receptors is predicted to counteract melanocortin activation of G␣s-coupled MC4R. AgRP acts in concert with NPY by blocking the binding of ␣-MSH to MC4R (8,13,14). The neurons that make NPY and AgRP also produce GABA, which inhibits POMC neurons and probably MC4R-bearing cells (15,16). Thus, these AgRP neurons are poised to inhibit melanocortin signaling by the neighboring POMC cells.The activation of melanocortin signaling by leptin inhibits appetite while stimulating metabolism (1, 2, 6). Consequently, the inactivation of mouse genes encoding leptin, leptin receptor, POMC, or MC4R leads to obesity (17)(18)(19)(20). However, the inactivation of genes encoding NPY, AgRP, or both has little effect on energy balance (21-23). These genetic results suggest that compensatory mechanisms in the KO mice mask the normal role of these peptides. Nevertheles...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Starvation after AgRP neuron ablation is independent of melanocortin signaling

Howell

Cowley

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

107

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“…26 The CNS agonist of MC4-Rs is a-MSH, a derivative of the pro-opiomelanocortin (POMC) precursor. 27 POMC neurons are found in the lateral part of the arcuate nucleus 28 and leptin receptor mRNA is coexpressed in a very high percentage of these arcuate nucleus neurons. 29 Furthermore, in leptin-deficient ob=ob mice or in fasted rodents (when leptin levels rapidly fall) POMC mRNA is markedly reduced.…”

Section: Leptin-responsive Cell Groupsmentioning

confidence: 99%

Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin

2001

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Leptin affects body weight by decreasing food intake, activating the sympathetic nervous system and regulating neuroendocrine function. This type of regulation is a hallmark of hypothalamic control, which typically integrates autonomic, endocrine and behavioral responses. We have performed a series of experiments investigating hypothalamic pathways underlying these actions of leptin. We found that leptin activates neurons that coexpress pro-opiomelanocortin (POMC) and cocaine-and amphetamineregulated transcript (CART) mRNA. These neurons innervate several sites, including sympathetic preganglionic neurons in the spinal cord, neurons in the paraventricular hypothalamic nucleus (PVH), and melanin-concentrating hormone and orexin neurons in the lateral hypothalamic area (LHA). Following leptin administration, POMC neurons express both Fos and suppressor of cytokine signalling-3 (SOCS-3) mRNA. In contrast, leptin induced SOCS-3 expression in neuropeptide Y (NPY) neurons but not Fos, suggesting that leptin acts differentially on NPY and POMC cells. We also investigated potential downstream targets of leptin responsive NPY and POMC neurons by assessing the distribution of the melanocortin 4 receptor (MC4-R) mRNA and Y1 and Y5 NPY receptor mRNA in chemically defined neurons. We found dense MC4-R mRNA expression in several sites including the PVH and LHA. Using dual-label in situ hybridization we found that MC4-R mRNA is coexpressed in PVH cells expressing pro-TRH mRNA. We also found Y1 and Y5 NPY receptor mRNA in the PVH in patterns very similar to that of MC4R, suggesting that these receptors may be coexpressed on at least some PVH neurons. These results provide a neuroanatomic framework explaining the endocrine, autonomic and behavioral effects of leptin.

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“…Some of its effects include pain blockade upon intravenous (15) and intraventricular (16) administration and suggestion of alterations in affect and mood' in manic, depressed (17), and schizophrenic (17) whether it produced its own fl-endorphin. During the past year a nonpituitary, brain fl-endorphin system has been described (18)(19)(20). This system also exhibits j3-lipotropin immunoreactivity (21,22) and corticotropin (ACTH)-like immunoreactivity (20,23), suggesting the existence in brain of the common 31,000 molecular weight precursor of (3-lipotropin/corticotropin that has been described in pituitary (24,25 Electrical stimulation of the brain has been shown to elicit analgesia in rat (26) and cat (27).…”

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Appearance of beta-endorphin-like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation.

Akil¹,

Richardson²,

Barchas³

et al. 1978

Proc. Natl. Acad. Sci. U.S.A.

150

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jt-Endorphin-like immunoreactivity in human ventricular cerebrospinal fluid was measured with a specific radioimmunoassay. The subjects were undergoing a surgical procedure for relief of chronic intractable pain. This procedure involved the focal stimulation of a medial thalamic site adjacent to the wall of the third ventricle. Samples were collected before and during the analgesic stimulation. No f-endorphin-like immunoreactivity could be detected prior to stimulation, suggesting that baseline levels are below 25 fmol/ml of cerebrospinal fluid. Electrical stimulation led to substantial increases (13-to 20-fold) in immunoreactive material in every subject. These results suggest that ,kendorphin-like material can be released into the ventricular system and may contribute to the pain blockade that results from periventricular stimulation.The isolation and characterization of f3-endorphin from camel (1), sheep (2), and human (2, 3) pituitaries rapidly led to its identification as an endogenous opioid (1-4). Administration of this 31-amino-acid peptide to laboratory animals results in phenomena like those associated with opiates, including naloxone-reversible analgesia (5-10), tolerance (8-11), and dependence (8,11 Electrical stimulation of the brain has been shown to elicit analgesia in rat (26) and cat (27). This analgesia bears many of the characteristics of opiate action, including partial reversal with the opiate antagonist naloxone (28-30) and the development of tolerance to and cross-tolerance with morphine (31). However, these effects are only partial, suggesting a role of nonopiate as well as opiate mechanisms in this method of pain control. This work has been extended to the human clinical situation. Patients suffering from chronic intractable pain derive long-term relief from the stimulation of medial thalamic and periaqueductal sites (32,33). Stimulation of a site in the vicinity of the posterior commissure, immediately adjacent to the ventricular wall at the level of the nucleus parafascicularis, has been found to combine excellent analgetic effectiveness with minimal side effects. The characteristics of the pain relief obtained from such stimulation have been described (32,33). This stimulation-induced analgesia in man also appears to have an opioid component, because it has been shown to be naloxone reversible (34, 35) and to be accompanied by a rise in enkephalin-like opioid material in the cerebrospinal fluid (CSF) (36). Because the stimulation site in humans is homologous to a region in rodents particularly rich in (3-endorphin activity, we have examined the effect of its stimulation on (3-endorphin immunoreactivity in CSF. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact. METHODS

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Evidence for two separate opiate peptide neuronal systems

Cited by 409 publications

References 21 publications

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Starvation after AgRP neuron ablation is independent of melanocortin signaling

Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin

Appearance of beta-endorphin-like immunoreactivity in human ventricular cerebrospinal fluid upon analgesic electrical stimulation.

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