The Influence of Photoperiod on the Hypothalamic Content of Beta-Endorphin and the Luteinizing Hormone Responses to Naloxone and to Steroid Withdrawal in the Male Syrian Hamster

The aim of this study was to investigate the influence of inhibitory photoperiods upon opioidergic function, as determined by changes in the hypothalamic content of β-endorphin and the luteinizing hormone response to opioidergic receptor blockade, in the male Syrian hamster over the course of gonadal involution and spontaneous gonadal recrudescence. Animals exposed to an 8 h light: 16 h dark cycle (8L: 16D) for 14 weeks underwent gonadal regression. Regression was also observed in animals held for 7 weeks on one of a range of short daylengths of between 11.5 h and 13.5 h, the degree of atrophy being greatest in those animals on the shortest daylength. The tissue concentration of β-endorphin within the mediobasal hypothalamus was significantly higher in animals exposed to 8L: 16D for 14 weeks than in gonadally active controls held on long days (16L: 8D). Exposure to photoperiods of less than 13.5 h for 7 weeks also caused a significant increase in the β-endorphin content of the mediobasal hypothalamus and there was a positive correlation between the concentration of β-endorphin, the degree of gonadal atrophy and the shortness of the photoperiod. Endorphin levels within the preoptic area were not affected by photoperiodic treatments. Exposure of intact animals to 8L: 16D for 12 weeks caused gonadal atrophy and an associated loss of the luteinizing hormone responses to both naloxone and castration. Castrated animals receiving testosterone replacement (cast + T) also exhibited photoinhibition, in the form of reduced serum levels of luteinizing hormone, and this was similarly accompanied by a loss of sensitivity to naloxone and to withdrawal of steroid. Prolonged exposure to 8L:16D led to spontaneous reactivation of the gonadotrophic axis as a consequence of the development of scotorefractoriness. In both gondally intact animals and in cast + T groups, this was associated with a restoration, in parallel, of the luteinizing hormone responses to naloxone and to castration/ steroid withdrawal. The time-course of the restoration of the response to steroid withdrawal in castrates was not significantly different to that observed in intact animals. The luteinizing hormone response to naloxone took significantly longer to redevelop in cast + T groups than it did in gonadally intact animals. The data demonstrate that central opioid systems are sensitive to photoperiod and are consistent with the hypothesis that opioids are involved in the neuroendocrine regulation of reproductive responses to daylength.     

Oral Absorption of Peptides: Influence of pH and Inhibitors on the Intestinal Hydrolysis of Leu-Enkephalin and Analogues

Leu-enkephalin (YGGFL) and several analogues were chosen as model peptides for the study of peptide absorption and hydrolysis in the rat jejunum. An HPLC assay was adapted to detect YGGFL or the analogues and metabolites. Peptide hydrolysis was studied in the rat jejunum using a single-pass perfusion method. Extensive hydrolysis of YGGFL was observed in the rat jejunum and approaches to reduce its metabolism were studied. The brush border enzymes are a major site of enkephalin hydrolysis. Lumenal peptidases were secondary to the brush border enzymes in hydrolyzing the enkephalins in this system. In the in situ perfusion system, YGGFL is hydrolyzed primarily to Tyr and GGFL by the brush border aminopeptidase and to YGG and FL by brush border endopeptidase. Lowering the jejunal pH below 5.0 significantly reduces aminopeptidase activity and, to a lesser extent, endopeptidase activity. An aminopeptidase inhibitor, amastatin, produced more pronounced inhibitory effects at higher pH and the endopeptidase inhibitors, tripeptides YGG and GGF, are effective even below pH 5.0. Coperfusion of YGGFL with a combination of aminopeptidase and endopeptidase inhibitors, e.g., amastatin and YGG, is more effective in inhibiting hydrolysis since both metabolic pathways are inhibited. Leu-D(Ala)²-enkephalin, while showing enhanced stability against aminopeptidase hydrolysis, is hydrolyzed at the Gly–Phe bond by the endopeptidase. Its hydrolysis is not affected by pH changes or amastatin but is decreased by YGG. The YGGFL wall permeability was estimated and is not a limiting factor for oral absorption.     

Antagonism of Stress-Induced Gastric Motor Alteration and Plasma Cortisol Release by Fedotozine (JO 1196) in Dogs

The effects of fedotozine (a new dimethyl propylamine derivative) on gastric motor inhibition and plasma cortisol increase induced by acoustic stress were investigated in fasted dogs fitted with strain-gauge transducers on the antrum and proximal jejunum and an implanted jugular catheter. Stress was induced by 1 hour of music (≤90 dB) played through earphones. Starting 40 to 50 minutes after the last migrating motor complex (MMC), acoustic stress delayed by 131% the next gastric MMC, whereas intestinal motility was unaffected. Plasma cortisol increased (p < 0.05) by 516%, 30 minutes after the beginning of noise. The inhibition of gastric MMC as well as the hypercortisolemia induced by acoustic stress were reduced in a dose-related manner or abolished by previous oral administration of fedotozine (0.1–1 mg/kg) but not by intravenous injection (0.1–0.5 mg/kg). The effect of fedotozine was abolished after previous intravenous treatment with MR 2266 (0.1 mg/kg). Only the motor effects were suppressed by naloxone (0.1 mg/kg i.v.), which induced a significant (p < 0.05) increase in plasma level. Bilateral truncal vagotomy, which suppressed the effects of acoustic stress on gastric motility but not on plasma cortisol, suppressed the antagonistic influence of fedotozine on hypercortisolemia. We conclude that fedotozine administered orally reduces both stress-induced gastric motor alterations and hypercortisolemia, probably by acting directly on K receptors present in the intestinal wall that activate vagal afferent fibers interacting, at the central nervous system level, with factors responsible for the gastric and endocrine alterations induced by stress.     

Stress-induced opioid analgesia and activity in mice: Inhibitory influences of exposure to magnetic fields

An exposure for 30 min to a 0.5 Hz rotating magnetic field (1.5–90 G) significantly reduced immobilization stress-induced, opioid analgesia and hyperactivity in CF-1 and C-57 BL strains of mice, respectively. The magnetic exposure also eliminated the day-night rhythm in stress-induced analgesia, with maximum inhibitory effects occurring in the dark period. Pre-treatment with naloxone (1.0 mg/kg) had comparable inhibitory effects on immobilization-induced analgesia and activity. These results suggest that exposure to magnetic stimuli can significantly influence stress-induced activation of endogenous opioid systems and their behavioral and physiological consequences.     

Discriminative stimulus effects of spiradoline,a kappa-opioid agonist

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED₅₀s for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.     

Endogenous Pain Modulation Profiles Among Individuals With Chronic Pain: Relation to Opioid Use

It is generally assumed that individuals exhibiting high pain inhibition also tend to exhibit low pain facilitation, but little research has examined this association in individuals with pain. The aims of this cross-sectional study were 1) to examine the association between measures of conditioned pain modulation (CPM) and temporal summation (TS) in individuals with chronic pain, and 2) to examine whether this association was moderated by demographic (age, sex), psychological (depression, catastrophizing), or medication-related (opioid use) variables. Individuals (N= 190) with back or neck pain completed questionnaires and underwent a series of quantitative sensory testing procedures assessing CPM and TS. Results indicated that individuals with higher levels of CPM showed lower levels of TS, r = –.20, P < .01. Analyses, however, revealed that the magnitude of this association was substantially weaker among opioid users (r= –.08, NS) than nonusers (r= ?.34, P < .01). None of the demographic or psychological variables included in our study influenced the association between CPM and TS. The magnitude of CPM was lower for opioid users than nonusers, suggesting that opioid use might dampen the functioning of endogenous pain-inhibitory systems and possibly contribute to a discordance between measures of pain inhibition and pain facilitation.

Prolonged gastric emptying half-time and gastric hypomotility after drug overdose

A prospective study was undertaken to determine if gastric motility and emptying are altered by the ingestion of overdoses of tricyclic antidepressants, acetaminophen, opioid-acetaminophen mixtures, carbamazepine or phenytoin. Gastric scintigraphy was used to measure gastric emptying half-time and assess gastric motility in 104 patients at initial presentation and again at follow-up (n = 85). Patients were imaged for 5 hours after being given 20 MBq of 99mTc tin colloid to drink. Drug serum levels were measured on all patients at initial presentation and at follow-up. We observed markedly prolonged gastric emptying half-times and severe hypomotility at initial presentation compared with follow-up in the vast majority of patients, except for a small group of patients with phenytoin poisoning. Twelve patients had gastric emptying half-times of over 300 minutes, a further 14 had half-times of over 200 minutes and 21 others had half-times of over 120 minutes. Poisoning is associated with hypomotility and a marked delay in gastric emptying that could influence the clinical course and patient management. These abnormalities may not be due to a direct effect of the ingested drug and factors such as stress may play a role.