A selective distribution pattern of different opiate receptors in certain areas of rat brain as revealed by in vitro autoradiography

Duka, T.; Schubert, Peter; Wüster, Michael; Stoiber, R.; Herz, A.

doi:10.1016/0304-3940(81)90368-2

Cited by 81 publications

(13 citation statements)

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“…Autoradiography provides an effective means to accurately map opiate-binding sites within the rat brain and correlate their distribution with brain regions known to mediate opiate actions (1-6). In addition, autoradiographic studies have greatly strengthened the suggestion that there are distinct ,u and 8 receptors (7-9), by demonstrating their unique regional distributions within the brain (10,11). Recently, we proposed that morphine and the enkephalins label three, not two, subpopulations of sites (12,13).…”

Section: Introductionmentioning

confidence: 99%

Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique.

Goodman¹,

Pasternak²

1985

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

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We have developed a quantitative computerized subtraction technique to demonstrate in rat brain the regional distribution of #1 sites, a common very-high-affinity binding site for both morphine and the enkephalins. Autoradiography provides an effective means to accurately map opiate-binding sites within the rat brain and correlate their distribution with brain regions known to mediate opiate actions (1-6). In addition, autoradiographic studies have greatly strengthened the suggestion that there are distinct ,u and 8 receptors (7-9), by demonstrating their unique regional distributions within the brain (10,11). Recently, we proposed that morphine and the enkephalins label three, not two, subpopulations of sites (12,13). In addition to the enkephalinpreferring 8 sites and the classical morphine-selective (p.2) sites demonstrated in the guinea pig ileum (7,14), there is a common site (p.l) to which both morphine and the enkephalins bind with very high affinity. This p.l site, corresponding to the high-affinity site identified in 1975 (15), differs from the pU2 and 8 sites developmentally, phylogenetically, biochemically, and pharmacologically, playing a major role in a number of important opiate actions, including supraspinal analgesia, but not in others, such as respiratory depression and most signs of physical dependence (12)(13)(14)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34).Homogenate binding studies reveal a heterogeneous distribution of Al sites in rat brain (31, 35), but they lack the necessary detailed resolution. Autoradiography, on the other hand, faced a number of difficulties, including the lack of a ligand that could selectively label pul sites. England Nuclear) in the absence or presence of morphine sulfate (5 nM). Nonspecific binding was determined from sections incubated with the radioligand and levallorphan (1 ,uM). A section from each group was stained with hematoxylin and eosin for use in identifying anatomical regions. Slides were washed twice for 5 min each in Tris buffer (0°C), dipped once in distilled water, dried with a stream of cold dry air, placed in an x-ray film cassette along with sections containing known concentrations of tritium (dpm/mg of tissue, dry weight), exposed to LKB Ultrofilm at 4°C with desiccant for 6 months, and developed. Standards were prepared as previously described (39).The autoradiographs of the tissue sections and standards were digitized by using a Vidion-based EYECOM II image processing system linked to a PDP11/23 computer. Multiple standards on each film varied by less than 5%. The correlation of optical densities of the standards to their activity levels (dpm/mg of tissue) were fit to a polynomial equation and used to calculate the concentrations of radioligand in the tissue sections (fmol/mg of tissue). Selected regions of the experimental sections were identified on adjacent sections stained with hematoxylin and eosin. Results represent averages of values determined in two to four areas of two sections of a rat b...

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Section: Introductionmentioning

confidence: 99%

Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique.

Goodman¹,

Pasternak²

1985

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

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“…the analgesic and respiratory effects of opiates (33,40), undergo developmental changes in number and affinity during the postnatal period (8,9,10,46). Subpopulations of opiate receptors (e.g., mu, delta, kappa, sigma) (27,29,3 1) may also show developmen<al changes but this possibility has yet to be examined.…”

Section: Discussionmentioning

confidence: 99%

“…In the sheep, the blood-brain barrier is effectively present by 125 days gestation (6). In adults animals, it is absent in the region of the area postrema (7) where endogenous opiate receptors (10,14,34,35) and the autonomic nuclei of the brainstem are located. The barrier is also absent in parts of the hypothalamus (7).…”

Section: Discussionmentioning

confidence: 99%

“…Methionine-enkephalin is found in autonomic ganglia (19,30,37), in the adrenal medulla (17,44), and in brain stem nuclei concerned with cardiopulmonary regulation (10,14,34,35). Our identification of maturational changes in the autonomic nervous system's response to methionine-enkephalin may be yet another important factor to consider in understanding the postnatal maturation of the autonomic nervous system (1, 3) as well as the pathophysiology of perinatal syndromes associated with autonomic nervous system imbalance, such as neonatal apnea (23).…”

Section: Discussionmentioning

confidence: 99%

“…Opioid receptors are located in these same areas, but are particularly abundant in regions associated with pain perception and pituitary hormone release (10,34,35) and in the medullary nuclei concerned with cardiopulmonary regulation (10,14,34,35). Opiate receptors also increase both in number and in affinity during the latter third of gestation and in the first few weeks after birth in rats (8,9,33).…”

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Maturation of Circulatory Responses to Methionine-Enkephalin

1983

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Summarydescending aorta and inferior vena cava, respectivelv. The fetalThe cardiovascular and respiratory effects of the naturally occurring endogenous opiate, methionine-enkephalin, were studied in 23 fetal sheep, five newborn lambs, 15 pregnant sheep, and four nonpregnant ewes. The opiate peptide produced dose-dependent decreases in heart rate and blood pressure in fetal and neonatal lambs but increased heart rate and blood pressure followed immediately by decreased heart rate and blood pressure in pregnant ewes. The circulatory responses were examined by pharmacologic blockade of receptor activity and by vagotomy. The bradycardia and hypotension in the fetus and tachycardia and hypertension in the adult were shown to be mediated by autonomic efferent nerves. Sinoaortic denervation did not affect the fetal responses to infused enkephalin. Respiration decreased in fetal as well as postnatal animals even at doses of methionine-enkephalin that did not significantly affect heart rate and blood pressure. These data indicate that the cardiovascular effects of infused enkephalins undergo maturational changes and are mediated by the autonomic nervous system.Endorphins and enkephalins are widely distributed throughout the brain, spinal cord, and peripheral autonomic nervous system (13, 37). Opioid receptors are located in these same areas, but are particularly abundant in regions associated with pain perception and pituitary hormone release (10,34,35) and in the medullary nuclei concerned with cardiopulmonary regulation (10,14,34,35). Opiate receptors also increase both in number and in affinity during the latter third of gestation and in the first few weeks after birth in rats (8,9,33). Because endogenous opiates, such as enkephalin, can modify cardiovascular and pulmonary function in adults (2, 5, 25, 36), we wished to assess whether there were developmental changes in circulatory regulation by endogenous opiates.To do this, we chose methionine-enkephalin as an opiate receptor agonist because it has been detected in high concentrations in the adrenal medulla (17, 44), is secreted into the circulation after appropriate stimulation (16,39, 41), and is found widely distributed in autonomic ganglia (19,30,37). In addition, because it is known that the autonomic nervous system matures postnatally (I, 3, 28), and that the enkephalins may function as cotransmitters with acetylcholine and catecholamines in autonomic ganglia and the adrenal medulla (18, 41), it is possible that maturational changes in the enkephalinergic system occur and may be important in modifying the cardiovascular response to stress. MATERIALS AND METHODSSurgery. Surgery was performed in 25 time-dated pregnant ewes at 120-130 days gestation (term is 145 + 5 days). Lower body anesthesia was accomplished by epidural injection of 2% tetracaine hydrochloride (Winthrop Laboratories, CA). The uterus was exposed through a midline incision and fetal hind limbs were delivered through a small hysterotomy. Polyvinyl catheters were inserted into both pedal arteries...

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Multiple Morphine and Enkephalin Receptors and the Relief of Pain

Pasternak

1988

JAMA

169

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A selective distribution pattern of different opiate receptors in certain areas of rat brain as revealed by in vitro autoradiography

Cited by 81 publications

References 13 publications

Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique.

Visualization of mu1 opiate receptors in rat brain by using a computerized autoradiographic subtraction technique.

Maturation of Circulatory Responses to Methionine-Enkephalin

Multiple Morphine and Enkephalin Receptors and the Relief of Pain

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