Region specific expression of NMDA receptor NR1 subunit mRNA in hypothalamus and pons following chronic morphine treatment.

The NMDA receptor has been implicated in opioid tolerance and physical dependence. Using in situ hybridization techniques, the effects of chronic morphine treatment on the expression of mRNAs encoding the NMDA receptor subunits NRI, NR2A, and NR2B were investigated. A significant increase in the level of the NR1 subunit mRNA was found in the locus coeruleus and the hypothalamic paraventricular nucleus following 3 days of intracerebroventricular (i.c.v.) morphine infusion (26 nmol microl(-1) h(-1)) through osmotic minipumps. No changes were detected in expression of the NRI mRNA in the frontal cortex, caudate-putamen, nucleus accumbens, amygdala, CA1, CA2, and the dentate gyrus of the hippocampus, and in the central grey after morphine treatment. The expression of NR2A and NR2B subunit mRNAs did not change after morphine treatment in any brain region. These results suggest that changes in gene expression of the NRI subunit of the NMDA receptor are involved in the development of morphine tolerance and dependence.

Mu- and delta-opioid receptor antagonists precipitate similar withdrawal phenomena in butorphanol and morphine dependence.

The relative involvement of mu- and delta-opioid receptors in the mediation of butorphanol-, as compared to morphine-, dependence was examined with the use of highly selective antagonists at mu- and delta-opioid receptors. Extracellular fluid levels of glutamate (Glu) and aspartate (Asp) were measured within the pontine locus coeruleus following precipitation of withdrawal from dependence on either butorphanol or morphine in conscious Sprague-Dawley rats. Dependence was induced by intracerebroventricular (i.c.v.) infusion of butorphanol (26 nmol/mu l/h), morphine (26 nmol/mu l/h) or saline vehicle (1 mu l/h) for 3 days by means of an osmotic minipump. Microdialysis probes (2 mm tip) were inserted into the locus coeruleus 24 h before precipitation of withdrawal by i.c.v. injection of either the mu-opioid receptor antagonist, D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; 48 nmol/5 mu l or 48 nmol/5 mu l), or the delta-opioid receptor antagonist, naltrindole (17-cyclopropy;methyl-6,7-dehydro-4,5-epoxy-3, 14-dihydroxy-6,7,2'3'-indolmorphinan hydrochloride; 48 nmol/5 mu l or 100 nmol/5 mu l). Baseline levels of Glu ranged from 9.59 + or - 1.27 to 12.84 + or - 3.01 mu M in the various treatment groups. Levels of Asp were similar. Precipitation of withdrawal by CTOP elicited significant increases of Glu and Asp in both morphine- and butorphanol-dependent rats. Maximal increases in Glu of 425% and 258% above baseline levels were elicited in the first 15 min microdialysis sample following i.c.v. injection of CTOP in morphine- and butorphanol-dependent rats, respectively. Behavioral signs of withdrawal were greater in morphine than butorphanol-dependent groups. The i.c.v. treatment with naltrindole elicited increases in Glu and Asp that were similar, although less marked, than those precipitated by CTOP treatment. Administration of naltrindole produced equivalent signs of withdrawal in both morphine- and butorphanol-dependent rats. Withdrawal from dependence on both morphine and butorphanol is characterized by elevations in coerulear levels of excitatory amino acids. Responses elicited following the use of selective mu- and delta-opioid receptor antagonists to precipitate withdrawal suggest that the role played by these receptors in mediation of the signs and symptoms of withdrawal do not differ greatly between butorphanol- and morphine-dependent rats.

Sucrose drinking reduces dorsal hypothalamic beta-endorphin levels in spontaneously hypertensive rats but not in Wistar-Kyoto rats.

The present study was performed to test whether drinking of a 10% sucrose solution would preferentially alter tissue content of beta-endorphin in dorsal and ventral hypothalamic fragments from the spontaneously hypertensive rat (SHR), as opposed to the Wistar-Kyoto rat (WKY). Changes were correlated with cardiovascular function and circulating catecholamine levels to assess the role of hypothalamic beta-endorphin, a putative mediator of sucrose-induced changes in cardiovascular sympathetic nervous tone. Male rats were trained to consume their total 24-h water intake in a single period between 0900-1100 h. Catheters were chronically implanted to sample blood and to record arterial blood pressure and heart rate. The experimental protocol consisted of a recording session, which included a 10-min drinking period wherein rats consumed 8 ml of either sucrose solution or deionized water. Rats were sacrificed and hypothalami removed for analysis of beta-endorphin content. Comparable increases in blood pressure were noted in SHR and WKY during drinking of either sucrose or water. Drinking-induced tachycardia was blunted in SHR drinking sucrose. Plasma norepinephrine was increased only in sucrose-drinking SHR. Plasma glucose levels were elevated in both SHR and WKY following drinking of sucrose, but not water. beta-Endorphin levels were reduced (p < 0.05) in dorsal, but not ventral, hypothalamic fragments only in SHR drinking sucrose. The sucrose-induced changes in beta-endorphin did not correlate with blood pressure responses. The results indicate an exaggerated stimulation of beta-endorphin release in the dorsal hypothalamus following sucrose ingestion in SHR.

Effect of weight loss on thiazide produced erectile problems in men.

Thiazide-type diuretics frequently produce erectile dysfunction in men on a regular diet. However, men on a weight-loss diet have much less erectile dysfunction. Thiazide-type diuretics also produce erectile dysfunction in rats and interfere with normal copulation. The mechanism of the dysfunction and the favorable response to weight loss is unknown.

Acute tachycardia and pressor effects following injections of kainic acid into the antero-dorsal medial hypothalamus.

The responses of systemic arterial blood pressure and heart rate to intra-cerebral injections of the excitatory neurotoxin, kainic acid, were examined in urethane-anesthetized rats. Injections of kainic acid into the antero-dorsal medial hypothalamus produced dose-related increases in both blood pressure and heart rate over a range of 30-1000 ng. Exophthalmos, mydriasis, increased respiratory rate and movements of the vibrissae were also noted. Injections of 1000 ng of kainic acid into the antero-dorsal medial hypothalamus produced significantly greater increases in blood pressure and heart rate than comparable injections of equimolar doses of the excitatory neurotoxins, quisqualic acid, N-methyl-D-aspartic acid or quinolinic acid. No differences in the magnitude of the cardiovascular responses to 1000 ng of kainic acid were detected between injections directed towards the paraventricular nucleus of the hypothalamus (PVN), lateral hypothalamus or lateral cerebral ventricle. In contrast, at doses of 30 ng, injections directed towards the paraventricular nucleus produced significantly greater responses than comparable injections into the lateral hypothalamus, medial thalamus or lateral cerebral ventricle. The distribution of radiolabelled kainic acid at this dose was found to extend ipsilaterally in the medial hypothalamus as far as 1 mm rostral and caudal to the injection site. The results suggest that excitation of neuronal cell bodies within the medial hypothalamus by excitatory neurotoxins produces acute increases in blood pressure and heart rate. However, widespread diffusion of kainic acid, in particular, was documented and caution in interpretation of the results produced by local intra-cerebral injections of this agent is recommended.

Vasopressin and renin response to plasma volume loss in spontaneously hypertensive rats.

Abnormalities in the vasopressin (VP) and renin-angiotensin systems have been described in spontaneously hypertensive rats (SHR). Responsiveness of these systems to a decrease in plasma volume was examined in the SHR at 6, 8, and 18 wk of age and compared with responses in age-matched normotensive Wistar and Wistar Kyoto rats (WKY). Trunk blood was collected 3 h after administration of 2 ml/100 g body wt of 0.9% saline, 15 or 30% polyethylene glycol (PEG), and in one group of conscious 8- and 18-wk-old rats, mean arterial pressure was monitored following PEG administration. Hematocrit and serum VP increased significantly in both strains at all ages following PEG. At 6 and 8 wk of age, the VP response to the PEG injection was significantly greater in SHR compared with WKY (P less than 0.005), but at 18 wk the response was comparable in the two strains. Serum renin activity (SRA) also increased in both strains receiving PEG at 6 and 8 wk of age, but the response was suppressed in the SHR relative to the WKY (P less than 0.001). At 18 wk of age, SRA increased in WKY, but the response was totally suppressed in SHR. Renal renin content in a separate group of rats was reduced in 19-wk-old SHR compared with WKY (P less than 0.001) but was not different in 5- and 8-wk-old rats. Thus there appears to be a hyperresponsiveness in the VP system in young SHRs that is not present in the renin-angiotensin system. The divergence in the responsiveness of the renin and VP systems and the attenuation of responsiveness in the VP system in 18-wk SHRs indicate a differential effect of the hypertensive process on the VP and renin systems in the SHR.

Modification of the cardiovascular response to enkephalin by preoptic-hypothalamic periventricular lesions.

The cardiovascular effects of central and peripheral injection of [D-Ala2]-methionine-enkephalin were examined in rats with electrolytic lesions of anteroventral third ventricle periventricular tissue (AV3V). Sham-operated rats demonstrated a biphasic increase in blood pressure and a tachycardia after intracerebroventricular injection and an increase in blood pressure following intravenous injection. AV3V-lesions blunted the initial component of the central pressor response but did not affect the peripheral response. The AV3V region appears to mediate a portion of the blood pressure response to central enkephalin. The cardiovascular effects of enkephalin are complex and are probably mediated by more than one locus in the central nervous system. Intracerebroventricular (icv) and intravenous (iv) injections of the methionine-enkephalin analogue [D-Ala2]-met-enkephalin (DAME) increase blood pressure in conscious rats (Rockhold, Crofton and Share, 1981). However, the central nervous system sites upon which enkephalins act to cause cardiovascular changes are not yet defined. A circumventricular organ, the organum vasculosum of the lamina terminalis (OVLT), is of particular interest in this regard. The OVLT contains neuronal elements which demonstrate enkephalin-like immunoreactivity (Finley, Maderdrut and Petrusz, 1980) and electrolytic lesions of periventricular tissue of the antero-ventral third ventricle (AV3V) region (which includes the OVLT) abolish the pressor response to icv administration of another peptide hormone, angiotensin II (Bealer, Phillips, Johnson and Schmid, 1979). Such data suggest that the AV3V region may play a role in enkephalin-induced cardiovascular changes. The present investigation examines cardiovascular effects following icv and iv administration of DAME in sham-operated and AV3V-lesioned rats.