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Biomedical subjects

J W Holaday

Publications and source records attributed to J W Holaday.

142 records · Page 8Linked to original sources
PubMed1977

Synchronized ultradian cortisol rhythms in monkeys: persistence during corticotropin infusion.

A highly synchronized ultradian cortisol rhythm with a predominant periodicity of 85 to 90 minutes was observed in eight isolated monkeys; this rhythm may be harmonically related to the circadian rhythm. The persistence of this synchronized rhythm during supramaximal infusions of adrenocorticotropin not only suggests that feedback is not causative but also challenges the classic concept that bursts of cortisol secretion are dependent upon an immediately preceding release of adrenocorticotropin.

Adrenocorticotropic Hormone↗
PubMed1977

beta-Endorphin: pituitary and adrenal glands modulate its action.

Hypophysectomized rats are supersensitive to the hypothermic effects of morphine and beta-endorphin injected intraventricularly as early as 1 week after surgery. At 2 weeks after surgery, there is a significant increase in the antinociceptive potency for these opiates. The route of opiate injection must be considered in interpretations of these results. The enhanced opiate potency following subcutaneous morphine injection in hypophysectomized rats may be partially explained by adrenal dysfunction, as demonstrated by a similar sensitization to subcutaneous morphine following adrenalectomy. By contrast, no enhancement of opiate potency was observed upon direct intraventricular injection of morphine or beta-endorphin in adrenalectomized rats. Furthermore, the potency of intravenous beta-endorphin is profoundly enhanced in adrenalectomized mice; five out of nine animals died when injected with a dose of the peptide that produced only mild analgesia in sham controls. The complete reversal of this intravenous beta-endorphin supersensitivity by dexamethasone implies a possible physiological interplay between the peptide and adrenal function.

Adrenal Glands↗
PubMed1977

Cortisol secretion and clearance in the rhesus monkey.

Cortisol secretory patterns were studied in two chair-adapted rhesus monkeys by simultaneous measurement of plasma concentration and specific activity of cortisol after an iv bolus of 14C-labeled hormone. The results indicated that fluctuating plasma cortisol concentrations are the result of episodic secretion by the adrenal cortex. Specific activity changes during these spontaneous secretory bursts indicated occasional submaximal activity. In addition, cortisol secretory rates calculated during basal (20.4 mug/min) and ACTH-stimulated (28.4mug/min) conditions in a total of seven monkeys were significantly different (P less than 0.05), further demonstrating that spontaneous secretory bursts were usually sub-maximal. From plasma samples collected at 10 min intervals, a cortisol distribution t1/2 of 6 min and a clearance t1/2 of 66 min were found. The apparent volume of distribution for this hormone was 4.8 liters, a value far in excess of extracellular fluid volume estimates. The circadian pattern of plasma cortisol in these monkeys resembled that reported for man, but monkeys had twice as many episodic bursts and over twice the mean cortisol levels as man. However, the 24 h production rate was 10.5 mg, a value within the range of human production.

Adrenal Cortex↗
PubMed1976

Relations between behavioral arousal and plasma cortisol levels in monkeys performing repeated free-operant avoidance sessions.

The commonly believed hypothesis that increases in adrenocorticoid levels sensitively reflect behavioral arousal was tested by subjecting monkeys to repeated sessions of free-operant avoidance; these sessions produced varying degrees of behavioral arousal over time, which were quantified by a behavioral scoring technique. Cortisol was reliably elevated only in the most aroused subjects early in the first avoidance session. Although subjects were still aroused later in the session, cortisol had returned to basal levels. During subsequent avoidance sessions, cortisol returned to basal levels and did not increase significantly even when arousal was further manipulated by the superimposition of unavoidable shock during the final avoidance session. The addition of unavoidable shock was associated with a significant correlation between arousal, as reflected by increases in response rate, and magnitude of change, usually decreases, in mean cortisol levels. The frequent occurrence of dissociations between cortisol levels and behavioral arousal, as reflected by behavioral score, operant rate, and shock frequency, indicates that cortisol levels are of little use as a neuroendocrine index of arousal.

Adrenocorticotropic Hormone↗
PubMedDate not supplied

The role of endogenous opioid peptides in the control of androgen levels in the male nonhuman primate.

Plasma androgen levels studied following the injection of the opioid agonists morphine sulfate (0.5-1.0 mg/kg), beta-endorphin (10-20 mg/kg), and [D-Ala2, D-Leu5]-enkephalin (DADLE; 5-20 micrograms/kg), and the opioid receptor antagonist naloxone (0.5-2.0 mg/kg) in nonrestrained adult male rhesus monkeys. Drugs were administered and blood samples were collected through indwelling jugular catheters. Morphine (1.0 mg/kg) and DADLE (10.0 micrograms/kg) decreased androgen levels by 70% and 34%, respectively. Significant decreases occurred 80 minutes after drug injections, and levels remained depressed for 180 minutes; beta-endorphin (20 micrograms/kg) produced no effect on androgen levels. Treatment with naloxone (0.5 mg/kg-2.0 mg/kg) alone produced marked increases in androgen levels. Peak hormone levels occurred 80 minutes after naloxone administration and remained elevated for up to 2 hours. The depressant effects of morphine and DADLE on androgen levels were completely reversed by the administration of naloxone (1.0 mg/kg). In monkeys pretreated with hCG, neither morphine (1.0 mg/kg) nor DADLE (20 micrograms-kg) had any effect on androgen levels for up to 3 hours after opioid administration. Administration of morphine or endogenous opioid peptides exerts negative effects on androgen levels, whereas antagonism or endogenous or exogenous opiates by naloxone results in increases in circulating androgens. These results support a physiologic role of the endogenous opioid peptides in primate reproductive function.

Androgens↗
PubMedDate not supplied

M 154,129, a putative delta antagonist, reverses endotoxic shock without altering morphine analgesia.

Studies were conducted with the putative delta opiate receptor antagonist M 154,129 to evaluate its potential for reversing circulatory shock without altering nociceptive processes. M 154,129 (30 mg/kg iv) did not alter tail flick or hot plate latencies by itself, nor did it alter the antinociceptive effects of morphine (4 mg/kg iv). Following endotoxic shock hypotension in conscious rats, M 154,129 (30 or 60 mg/kg iv) produced a rapid return of arterial pressure to pretreatment levels. These data indicate that circulatory shock may be mediated at delta opioid receptors. Moreover, delta antagonists may have therapeutic benefit in reversing shock without intensification of pain.

Analgesia↗
PubMedDate not supplied

Repeated electroconvulsive shock or chronic morphine treatment increases the number of 3H-D-Ala2,D-Leu5-enkephalin binding sites in rat brain membranes.

Experiments were performed in rats to evaluate the possible mechanisms responsible for the pharmacological cross-sensitization observed between repeated electroconvulsive shock (ECS) and chronic morphine administration. Repeated daily ECS for 9 days as well as chronic morphine pellet implantation resulted in a significant increase in the number of 3H-DADLE binding sites (Bmax values of 231 and 196 fmoles/mg protein, respectively). By contrast, single ECS, repeated sham ECS, and placebo pellet-treated rats all had significantly lower Bmax values (approx. 170 fmoles/mg protein). Affinities were not significantly altered by these treatments (Kd values between 3.1 and 4.0 nM). These data may link pharmacological cross-sensitization (repeated ECS and chronic morphine treatment) with a functional increase in the number of available opioid receptors.

Animals↗
PubMedDate not supplied

Cardiorespiratory effects of mu and delta opiate agonists following third or fourth ventricular injections.

The cardiorespiratory effects of prototype mu (morphine and beta-casomorphine 1-4) and delta (D-Ala2-D-Leu5Enkephalin-DADLE) opioid ligands were compared following microinjection into third and fourth ventricular spaces in conscious and anesthetized rats. The direction of change in arterial pressure produced by ventricular opioid injections varied according to ligand, site of administration, and state of consciousness of the animal. In general, pentobarbital anesthesia blocked or reversed the pressor response to these opiate agonists; depressor responses became magnified following pentobarbital. Qualitatively, the predominant effect of third ventricular DADLE in anesthetized rats was to produce a depression of arterial pressure and pulse pressure, suggesting an involvement of hypothalamic delta opioid receptors in decreasing sympathetic outflow. By contrast, morphine exerted pronounced bradycardic effects following fourth ventricular administration, suggesting an action at mu opioid receptors which influence vagal parasympathetic activity. Both ligands lowered respiratory rates upon fourth ventricular injection, indicating a possible involvement of either opioid receptor subtype in the depression of brainstem respiratory centers. These depressant effects of opioids upon cardiorespiratory function were readily reversed by naloxone. The qualitative similarity between the cardiovascular effects of third ventricular DADLE administration and various forms of circulatory shock may indicate that both phenomena involve delta opioid receptors at hypothalamic sites.

Animals↗
PubMedDate not supplied

Pituitary opioid involvement in ECS-postictal electrogenesis and behavioral depression in rats.

The role of pituitary opioids in electroconvulsive shock (ECS)-induced postictal electrogenesis and behavioral depression was investigated in sham-hypophysectomized and hypophysectomized rats. These animals were divided into two subgroups and injected SC with either saline or naloxone (3 mg/kg) 10 min prior to transauricular ECS. Sham-hypophysectomized rats given saline responded to a single ECS with a 65 +/- 18% (s.e.) increase in postictal electrogenesis and a behavioral depression lasting 3840 +/- 530 sec. Naloxone significantly antagonized both the postictal increase in EEG voltage output and behavioral depression. Hypophysectomy by itself was without effect on EEG patterns and only partially attenuated the ECS-induced electrogenesis and postictal depression (31.9 +/- 9% and 2360 +/- 511 sec, respectively). However, in hypophysectomized rats, naloxone did not further antagonize these effects of ECS. Thus, it appears that pituitary opioids may, at least in part, mediate postictal electrogenesis and behavioral depression. Alternatively, since hypophysectomy only partially attenuates these phenomena, central or nonpituitary opioid peptide systems may be involved. In view of the observed decrease in responsiveness to naloxone in hypophysectomized rats, nonopioid systems cannot be ruled out as contributors to the opioid-like effects of ECS in these animals.

Animals↗
PubMedDate not supplied

Cardiovascular effects of dynorphin A (1-13) in conscious rats and its modulation of morphine bradycardia over time.

The short-term cardiovascular effects of dynorphin A (1-13), as well as its effects upon morphine bradycardia were investigated. In unanesthetized, unrestrained rats, intracerebroventricular (ICV) dynorphin A (1-13) injections (10-20 micrograms) produced a dose-related pressor effect, whereas intravenous (IV) dynorphin A (1-13) (1.0 mg/kg) produced a depressor effect; these responses persisted less than five min. Heart rate was not significantly altered by these doses or routes of administration. Dynorphin A (1-13) also produced behavioral effects in the unanesthetized animals, such as wet dog shakes in response to IV administration and wet dog shakes accompanied by barrel rolling in response to ICV administration. To evaluate the effects of dynorphin A (1-13) pretreatment on the bradycardic response to IV morphine, rats were pretreated with 10 micrograms dynorphin A (1-13) ICV four, six or eight hours prior to challenge with morphine sulfate (0.1 mg/kg IV). Four hour pretreatment with dynorphin A (1-13) (tested at 14:00 hr) resulted in a potention of morphine bradycardia, with six hours pretreatment (tested at 16:00 hr) no effect was observed, and eight hours following dynorphin A (1-13) pretreatment (tested at 18:00 hr) morphine bradycardia was attenuated. Additionally, the bradycardic response to IV morphine alone became more exaggerated as rats approached their nocturnal activity cycle. These data further establish that dynorphin A (1-13) exerts a potent, long lasting modulatory effect on morphine bradycardia and emphasize the importance of circadian variables in altering the magnitude of cardiovascular responses to opioid agonists.

Analysis of Variance↗
PubMedDate not supplied

Anticonvulsant effects of mu (DAGO) and delta (DPDPE) enkephalins in rats.

The effects of highly selective mu and delta opioid peptide agonists were determined in two rat models of experimentally-induced convulsions, the flurothyl threshold test and the maximal electroshock test. Intracerebroventricular injections of the mu selective enkephalin DAGO (0.3-2.2 nmol) resulted in a dose-related protection in both seizure models. Pretreatment with a low dose of naloxone (29 nmol) or the irreversible mu antagonist beta-FNA (21 nmol), but not the delta opioid antagonist ICI 154,129 (50 nmol), antagonized the anticonvulsant actions of DAGO. Intracerebroventricular injections of the delta selective enkephalin DPDPE (70-140 nmol) also resulted in seizure protection. These effects were selectively antagonized by the delta antagonist ICI 174,864 (2.8 nmol), but not by pretreatment with beta-FNA. Thus, using agonists and antagonists highly selective for mu and delta opioid receptors, anticonvulsant actions of enkephalin have been described against chemically- and electrically-induced convulsions in rats.

Animals↗
PubMedDate not supplied

Hindlimb paralytic effects of arginine vasopressin and related peptides following spinal subarachnoid injection in the rat.

Intrathecal (IT) injection of arginine vasopressin (AVP) in rats caused a transient (less than 30 min), dose-related paralysis of the hindlimbs, loss of hindlimb and tail nociceptive responsiveness, and increased mean arterial pressure. Motor dysfunction was produced with comparable potency by lysine vasopressin (LVP) and arginine vasotocin (AVT); oxytocin (OXY) was approximately 1000 times less potent. Paralysis induced by these peptides was selectively blocked following IT pretreatment with 0.5 nmoles of the vasopressin V1 receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine] Arg8-vasopressin (d(CH2)5[Tyr(Me2)]AVP). Pressor and antinociceptive responses to AVP were also blocked by this compound. However, at higher doses (2-5 nmoles, IT), d(CH2)5[Tyr(Me2)]AVP produced hindlimb paralysis, antinociception, and pressor responses by itself. In contrast to the fiber degeneration, cell loss, and necrosis found in lumbosacral cords of rats persistently paralyzed by other peptides (dynorphin A, somatostatin, and ICI 174864), neuropathological changes were not evident in spinal cords of rats transiently paralyzed by IT AVP. These results indicate that AVP-related peptides affected diverse spinal cord functions through interactions with a V1-like receptor. The similar pattern of cardiovascular and antinociceptive responses to other peptides (dynorphin A, somatostatin, and ICI 174864), which also caused hindlimb paralysis, suggests that the former responses may actually reflect the nonselective consequences of a peptide-induced disruption of spinal cord function, rather than specific shared pharmacological effects.

Animals↗
PubMedDate not supplied

Intravenous beta-endorphin: behavioral and physiological effects in conscious monkeys.

Beta-endorphin (0.7 and 2.8 mg/kg) and morphine (0.15 and 0.60 mg/kg) were administered intravenously to rhesus monkeys responding on an operant schedule. Beta-endorphin injections resulted in dose-dependent effects which included marked, but relatively brief disruptions in behavioral responding, decreases in systolic blood pressure, and more protracted increases in heart rate. Morphine injections were followed by much longer duration decreases in response rates and systolic blood pressure, and an irregular but largely deceleratory heart rate response. On a molar basis, beta-endorphin was approximately twice as potent as morphine. It was concluded that intravenously administered beta-endorphin exerts behavioral and physiological effects in the unanesthetized primate.

Animals↗
PubMedDate not supplied

Upregulation of the opioid receptor complex by the chronic administration of morphine: a biochemical marker related to the development of tolerance and dependence.

Studies conducted after the development of the rapid filtration assay for opiate receptors, and before the recognition of multiple opioid receptors, failed to detect changes in opioid receptors induced by chronic morphine. Recent experiments conducted in our laboratories were designed to examine the hypothesis that only one of several opioid receptor types might be altered by chronic morphine. Using binding surface analysis and irreversible ligands to increase the "resolving power" of the ligand binding assay, the results indicated that chronic morphine increased both the Bmax and Kd of the opioid receptor complex, labeled with either [3H][D-Ala2,D-Leu5]enkephalin, [3H][D-Ala2-MePhe4,Gly-ol5]enkephalin or [3H]6-desoxy-6 beta-fluoronaltreone. In the present study rats were pretreated with drugs known to attenuate the development of tolerance and dependence [the irreversible mu-receptor antagonist, beta-funaltrexamine (beta-FNA), and the inhibitor of tryptophan hydroxylase, para-chlorophenylalanine], prior to subcutaneous implantation of morphine pellets. The results demonstrated that 1) unlike chronic naltrexone, beta-FNA failed to upregulate opioid receptors and 2) both beta-funaltrexamine and PCPA pretreatment attenuated the chronic morphine-induced increase in the Bmax, but not the Kd, of the opioid receptor complex. These results provide evidence that naltrex-one-induced upregulation of the opioid receptor complex might occur indirectly as a consequence of interactions at beta-funaltrexamine-insensitive opioid receptors and that morphine-induced upregulation (increased Bmax) of the opioid receptor complex is a relevant in vitro marker related to the development of tolerance and dependence. These data collectively support the hypothesis that endogenous antiopiate peptides play an important role in the development of tolerance and dependence to morphine.

Amino Acid Sequence↗