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Biomedical subjects

H Akil

Publications and source records attributed to H Akil.

296 records · Page 17Linked to original sources
PubMedDate not supplied

Gamma-melanotropin response to ovine corticotropin releasing factor in normal humans.

Plasma gamma-melanotropin was measured by a gamma 3MSH-specific radioimmunoassay before and after a single bolus intravenous infusion of ovine corticotropin releasing factor (oCRF; 0.1 microgram/kg) in seven normal men. A significant increase of gamma 3MSH was observed 15 minutes post-oCRF infusion, which paralleled a similar increase in plasma cortisol. Gel filtration chromatography revealed that the observed increase was attributable to elevations of 9K and 4K forms of gamma 3MSH immunoreactivity. Affinity chromatography demonstrated that the majority of gamma 3MSH immunoreactivity in human plasma is glycosylated. As the smaller forms of gamma 3MSH are felt to have endocrine activity at the adrenal cortex, these changes may be physiologically relevant.

Adult↗
PubMedDate not supplied

Dynorphin immunocytochemistry in the rat central nervous system.

The distribution of dynorphin in the central nervous system was investigated in rats pretreated with relatively high doses (300-400 micrograms) of colchicine administered intracerebroventricularly. To circumvent the problems of antibody cross-reactivity, antisera were generated against different portions as well as the full dynorphin molecule (i.e., residues 1-13, 7-17, or 1-17). For comparison, antisera to [Leu]enkephalin (residues 1-5) were also utilized. Dynorphin was found to be widely distributed throughout the neuraxis. Immunoreactive neuronal perikarya exist in hypothalamic magnocellular nuclei, periaqueductal gray, scattered reticular formation sites, and other brain stem nuclei, as well as in spinal cord. Additionally, dynorphin-positive fibers or terminals occur in the cerebral cortex, olfactory bulb, nucleus accumbens, caudate-putamen, globus pallidus, hypothalamus, substantia nigra, periaqueductal gray, many brain stem sites, and the spinal cord. In many areas studied, dynorphin and enkephalin appeared to form parallel but probably separate anatomical systems. The results suggest that dynorphin occurs in neuronal systems that are immunocytochemically distinct from those containing other opioid peptides.

Animals↗
PubMedDate not supplied

The preferential release of beta-endorphin from the anterior pituitary lobe by corticotropin releasing factor (CRF).

Although a number of investigators have shown that release of ACTH is accompanied by the release of Beta-endorphin (beta-End) and Beta-lipotropin (beta-LPH), the proportion of the latter two peptides released with stress or by CRF is unclear. To evaluate directly the release of beta-End versus beta-LPH from the anterior lobe, we used molecular sieving of plasma and subsequent radioimmunoassay to measure release of both beta-End and beta-LPH into plasma after thirty minutes of inescapable intermittent footshock. We found a substantial increase in circulating beta-End which appears to be of anterior lobe origin. The beta-End does not appear to represent peripheral conversion of beta-LPH to beta-End since the ratio of beta-LPH:beta-End released remained constant between five and thirty minutes of stress, and the rate of disappearance of beta-LPH is slower than the rate of disappearance of beta-End following the termination of stress. Further confirmation of these findings was obtained by examining the POMC derived peptides released by pituitary cell suspensions in the presence and absence of oCRF. While unstimulated release consisted of equal proportions of beta-End and beta-LPH, stimulation of the anterior lobe cell suspensions with oCRF resulted in the release of two-fold more beta-End than beta-LPH.

Animals↗
PubMedDate not supplied

The degradation of dynorphin A in brain tissue in vivo and in vitro.

The demonstration of analgesia following in vivo administration of dynorphin A (Dyn A) has been difficult. In contrast, a number of electrophysiological and behavioral effects reported with in vivo injection of Dyn A can be produced by des-tyrosine dynorphin A (Dyn A 2-17). This suggested the extremely rapid amino terminal degradation of dynorphin A. To test this hypothesis, we examined the degradation of dynorphin A following in vivo injection into the periaqueductal gray (PAG) as well as in vitro using rat brain membranes under receptor binding conditions. In vivo, we observed the rapid amino terminal cleavage of tyrosine to yield the relatively more stable destyrosine dynorphin A. This same cleavage after tyrosine was observed in vitro. Inhibition of this aminopeptidase activity in vitro was observed by the addition of dynorphin A 2-17 or dynorphin A 7-17 but not after the addition of dynorphin A 1-13, dynorphin A 1-8, dynorphin B or alpha-neo-endorphin suggesting a specific enzyme may be responsible. The detection of the behaviorally active des-tyrosine dynorphin A following in vivo injection of dynorphin A suggests that this peptide may play an important physiological role.

Animals↗
PubMedDate not supplied

[D-Ala2, (F5) Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN): a potent analog of dynorphin 1-13.

Intracerebroventricular administration of the dynorphin analog, [D-Ala2,(F5)Phe4]-dynorphin 1-13-NH2 (DAFPHEDYN) in rats produced diuresis and profound analgesia. Both effects were antagonized by central administration of naltrexone or naloxone. Intravenous administration of 10, 25, and 50 mg/kg of DAFPHEDYN failed to induce diuresis. The increased potency of DAFPHEDYN was apparent from the failure of an equal dose of the parent compound (dynorphin 1-13) to produce diuresis and the failure of [D-Ala2]-dynorphin 1-13-NH2 to produce analgesia. Radioligand binding studies indicated the DAFPHEDYN retains the same degree of kappa selectivity as the parent compound (dynorphin 1-13) though a drop in affinity occurred. DAFPHEDYN may be of significant interest because it retains the essential pharmacology of the parent compound and exhibits marked in vivo potency.

Analgesia↗
PubMedDate not supplied

Delta opioid receptor mRNA distribution in the brain: comparison to delta receptor binding and proenkephalin mRNA.

The recent cloning of the mouse delta opioid receptor (Evans et al., 1992; Kieffer et al., 1992) has demonstrated it to be a member of the seven transmembrane G-protein coupled family of neurotransmitter receptors. The present study describes the cellular localization in the central nervous system (CNS) of an mRNA encoding this receptor and compares it with the distribution of delta receptor binding and proenkephalin mRNA using a combination of in situ hybridization and receptor autoradiographic techniques. Delta receptor mRNA was visualized with a cRNA probe (472-903 bp) corresponding to transmembrane domains III-VI of the receptor, while proenkephalin mRNA was labeled with a cRNA probe to exon 3 (139-832 bp). A high level of correspondence was observed between the distribution of delta receptor mRNA and delta receptor binding as defined by the selective ligand [3H]D-Pen2-Pen5-enkephalin. Delta receptor mRNA and binding were expressed in the neocortex, caudate-putamen, nucleus accumbens, olfactory tubercle, diagonal band of Broca, amygdala and the nucleus of the solitary tract. Discrepancies in the distribution of delta receptor mRNA and binding in the olfactory bulb, hippocampus, globus pallidus and substantia nigra pars reticulata, may in part be due to differential receptor synthesis and transport. These results are discussed in relation to the distribution of proenkephalin mRNA and how this may affect our understanding of opioid circuitry in the CNS.

Animals↗
PubMedDate not supplied

Long term results of periventricular gray self-stimulation.

Thirty patients were operated upon, with chronic implantation of self-stimulating devices for stimulation of the posterior periventricular gray matter for pain control. Three patients required removal of the electrodes because of failure of adequate pain control during the period of percutaneous testing, and five patients report on long term follow-up that they have had no pain relief with stimulation, and have discontinued it. Four patients describe minor relief of pain, and 18 patients report significant relief of pain with stimulation. Therefore, 18 patients, or 66% of the 27 patients having implantation, are considered to have had successful operations, and 12 of the patients are considered failures. Stimulation for brief periods of time, such as 5 to 30 minutes every 2 to 12 hours has been found adequate for control of chronic pain with minimal side effects and a low complication rate.

Analgesia↗