Maurice Hirst

Suppression of food intake and body weight gain by naloxone in rats.

Abstract The effect of acute and chronic administration of naloxone on food acquisition and weight gain in rats was studied in 3 experiments. One injection of a sparingly-soluble salt of naloxone in slow-release vehicle markedly lowered mean food intake over that of control rats injected with the vehicle only. Mean body weight of the naloxone-injected rats was significantly lower than that of the control group for one week. Repeated evening injections (2000 h) of naloxone hydrochloride in saline tended to reduce the night-time feeding below control levels throughout the 10-day period of naloxone administration. Food intake was significantly lower in the 4- and 8-h periods after the first injection of naloxone than that on the preceding saline control night. The initial decreases were offset by increased day-time feeding so that total daily food intake was not significantly altered over the 10 days. When saline was substituted for naloxone, food intake increased. Rats given naloxone following 24 h of fasting consumed significantly less food and gained less weight during 4 h of access to food compared to those receiving saline. After a 48-h fast naloxone-treated rats also gained significantly less body weight than those given saline, but the reduction in food intake was not statistically significant. These results suggest the possibility that endorphins may have a modulating effect on feeding activity.

Daily rhythms of analgesia in mice: effects of age and photoperiod

Abstract Daily rhythms in respone to aversive thermal stimulation and the analgesic effectiveness of morphine were assessed by the hot-plate method with young (1–2 months), mature (8–12 months) and old (20–30 months) mice exposed to various light-dark conditions (LD 12:12; 16:8; 8:16 h). The patterns of response after saline or morphine varied with the specific light-dark conditions examined, but routinely, there were increases in response latency from the early portions of the light phase to later time, and a further enhancement of the time to respond with onset of the dark phase. The dark-phase response declined abruptly with the start of the light-phase. Significant age-related declines were observed in the elevated, dark-phase morphine-analgesic and basal aversive responses, with no consistent effects of age evident in the light-phase.

Social conflict activates opioid analgesic and ingestive behaviors in male mice

The activation of endogenous opioid mechanisms and their subsequent effects on rodent behavior and physiology has usually been characterized following artificial stress. In this study the more naturalistic stress arising from social conflict between male mice was used to investigate the involvement of opioid systems in post-conflict analgesic and ingestive behaviors. Both the aggressive encounters and the subsequent defeat experience resulted in marked analgesia and the induction of ingestive behaviors. Feeding and drinking responses were analogous to those observed after administrations of either the endogenous opioid peptide, beta-endorphin, or the exogenous opioid agonist morphine. The ingestive behaviors following defeat or central opiate administration were blocked by the opiate antagonist naloxone. The present results support the hypothesis of a direct activation of the endogenous opiate system following social conflict.

OCCUPATIONAL EXPOSURE TO CYCLOPHOSPHAMIDE

Several lines of research have demonstrated the risk of occupational exposure of health-care personnel to anticancer drugs. Urine samples from two nurses working in a cancer clinic were analysed for cyclophosphamide (CP) by gas chromatography after they had prepared the drug for treatment. Since the drug might be absorbed through the skin, urine samples from five volunteers were also examined after a solution of CP had been applied topically to the cubital fossa area. Variable quantities of intact CP were identified in samples from the volunteers collected over 24 h, but in most cases the drug was evident only in urine samples given more than 6 h after application. CP was found in several urine samples from the nurses, but the quantities of CP in these samples were not related to the amounts of drug handled. The identity of CP was confirmed by gas-chromatography/mass-spectrometry. CP appeared sooner in the urine samples from the nurses than in those from the volunteers, suggesting a faster route of absorption, perhaps through inhalation of aerosols generated during dissolution of the drug. These findings suggest that the increased levels of mutagenicity observed in urine samples of nurses who worked on oncology wards might have arisen, in part, from metabolites of CP.

Ageing, opioid analgesia and the pineal gland.

The effects of ageing on day-night rhythms of analgesia was examined with young (1-2 months), mature (8-12 months) and old (20-30 months) mice. Significant age-related declines were observed both in the absolute levels and diel rhythms of morphine analgesia, with the most pronounced changes occurring at night. Administration of the pineal hormone, melatonin, augmented day-time levels of analgesia in all age classes and reversed the age-related decline in nocturnal morphine analgesia in old mice. Inhibition of pineal function in young mice by either exposure to light pulses or treatment with benserazide mimicked the effects of ageing on nocturnal morphine analgesia. These findings suggest that the pineal gland and melatonin are involved in modulating diel rhythms of analgesia and have an influential role on age-related changes in opioid responses.

Effect of intrahypothalamic injection of [D-Ala2,D-Leu5]enkephalin on feeding and temperature in the rat

The effectiveness of the delta-opioid agonist [D-Ala2,D-Leu5]enkephalin (DADLE) in eliciting alterations in feeding and core temperature in rats was compared to morphine. When injected into the ventromedial hypothalamus this peptide caused a dose-related increase in feeding which was rapid in onset and of short duration, and a short-lived increase in temperature. Neither of these effects was blocked by the intrahypothalamic injection of naloxone. The alpha-adrenoreceptor antagonist phentolamine significantly reduced DADLE-stimulated feeding, although it did not counteract the hyperthermia. Since the delta-opioid agonist DADLE is more potent than the mu-agonist, morphine, and produces its effect more rapidly, the delta-opiate receptor may have an influence on the regulation of feeding.

Magnetic fields abolish the enhanced nocturnal analgesic response to morphine in mice.

Mice given morphine displayed diel rhythms in the latency of their behavioral response to placement on a hot plate, there being a several fold increase in their nocturnal reaction times. Exposure to a rotating magnetic field eliminated the day-night analgesia rhythms, reducing over 5-10 days the enhanced nocturnal latencies to those found during the day. The attenuation returned to normal nocturnal levels several days after removal of the rotating magnetic field and could be subsequently re-established by reapplication of the magnetic field condition. It is suggested that these changes in analgesia may reflect alterations in the activity of the pineal gland during exposure to magnetic fields.

FMRFamide, a putative endogenous opiate antagonist: evidence from suppression of defeat-induced analgesia and feeding in mice.

Social conflict and defeat in mice leads to an activation of endogenous opiate systems. The effects of intracerebroventricular administration of the peptide FMRFamide (Phe-Met-Arg-Phe-NH2) and the opiate antagonist naloxone, on aggressive encounters, defeat-induced analgesia and defeat-induced feeding were examined in male mice. Both substances reduced the number of bites required to cause defeat in subordinate mice during aggressive encounters, as well as suppressing the subsequent defeat-induced analgesia. Administration of FMRFamide or naloxone also reduced defeat-induced feeding. These results indicate that FMRFamide (or FMRFamide-like neuropeptides) may function as endogenous opioid antagonists.

Reduced nocturnal morphine analgesia in mice following a geomagnetic disturbance

Latency to respond to an aversive thermal stimulus and the degree of analgesia induced by morphine were examined in mice injected with either isotonic saline or morphine sulfate (10 mg/kg) during midscotophase of a 12:12 h LD cycle. When mean response latencies were compared to the degree of geomagnetic disturbance (Ap index) present on test days, it was found that during the geomagnetic storm on December 17th, 1982, a significant reduction (P less than 0.01) in response latency was evident in both saline- and morphine-treated mice. The reduction in response latencies was greater, and lasted longer in the morphine-treated animals. It is suggested that the pineal gland may mediate this biomagnetic effect.

Brain and serum levels of naloxone following peripheral administration

Striatal, hypothalamic and serum concentrations of naloxone were measured by a new high-performance liquid chromatographic procedure at various time up to 120 min following subcutaneous administration of 1, 5, and 10 mg naloxone hydrochloride/kg to rats. A dose-concentration relationship was evident throughout. Peak levels were observed at the first measurement time (15 min) and tissue values were consistently higher than concentrations in serum. The correlations between serum and brain naloxone levels suggests that in normal rats central concentrations of the drug can be extrapolated from serum concentrations.