Faculty Bibliography

We have previously found rat and toad (Bufo marinus) brain to contain inverse ratios of benzomorphan-preferring (kappa/sigma) and morphine-preferring (mu) opioid receptor types. The aim of the present study was to compare in vivo pharmacologic activity of a benzomorphan, ethylketocyclazocine (EKC) and morphine sulfate (MS) in rat and toad. Footshock intensity thresholds for eliciting locomotion were determined and dose-response curves for EKC and MS analgesia were obtained. Drugs were injected subcutaneously. In rats (high mu, low kappa in brain), both compounds produced analgesia and displayed similar sensitivity to naloxone antagonism. The analgesic effects of EKC and MS may, therefore, be mediated by a common receptor type (mu) in this pain test in rats. In toads (high kappa, low mu in brain), MS produced naloxone-reversible analgesia at doses 20-fold higher than were effective in rats. Toads did not display EKC analgesia at doses below those producing motor impairment. Moreover, 50-fold higher doses were required to produce such impairment in toads. Thirty minutes following subcutaneous injection of 3H-EKC, similar concentrations were found in rat and toad brain. Uptake into brain is probably not a factor in the behavioral resistance of toads to EKC

In tests of frequency threshold for brain stimulation-induced feeding, naloxone (s.c.) did not affect the first in a brief series of threshold estimates but elevated subsequent estimates progressively. It was demonstrated that neither the time-course of drug action nor any cumulative disruptive effect of brain stimulation itself, accounts for the progressive elevation of threshold. Self-stimulation in 'feeding' electrodes was therefore studied, in combination with hunger manipulations, to inferentially evaluate naloxone's effect on feeding mechanisms. Results suggest naloxone's anoretic effect does not reflect heightened responsiveness of a satiety mechanism. Reversal by naloxone of the potentiating effect of hunger on self-stimulation, however, suggests the anoretic effect is due to blockade of an opioid process associated with hunger that otherwise enhances the reward value of food

The topics discussed in this article are the neural mechanisms of opiate hedonic effects and the role of endogenous opioids in regulating motivational-affective responses of the organism. First, research on the mechanisms of opiate hedonic effects is briefly reviewed; evidence is discussed which suggests the existence of separate neural substrates for the mediation of opiate analgesia, amelioration of aversive emotion, and reward. In the remainder of the article, recent work of our laboratory is summarized which concerns the role of endogenous opioids in regulating feeding and reward elicited by electrical stimulation in the lateral hypothalamus; evidence is presented which indicates that opioid activity associated with the state of food motivation potentiates reward processes. In addition, evidence is discussed which suggests that this opioid activity may concurrently diminish the organism's emotional responsiveness to competing aversive stimuli. The relevance of this area of research to human opiate abuse is discussed.

Feeding was induced in rats by electrical stimulation in the lateral hypothalamus. Naloxone (0.2 and 1.0 mg/kg) produced a dose-related elevation of the frequency threshold for stimulation-induced feeding while quarternary naloxone (2.0 and 10.0 mg/kg) had no effect. Since quarternary naloxone does not readily penetrate the blood-brain barrier, we conclude that the opiate receptors at which naloxone exerts its anorectic action are located in the brain rather than in potential peripheral tissues such as gastrointestinal tract, pancreas or adrenal medulla. The threshold-elevating effect of naloxone only became marked after rats had engaged in one or two 5-sec bouts of feeding. The effect continued to increase following each subsequent bout of feeding. Naloxone therefore appears to inhibit feeding by interacting with post-ingestive factors

We have previously shown that feeding induced by electrical stimulation in the lateral hypothalamus of rats is inhibited by naloxone but not its quaternary analogue. In the present study, effects of morphine and loperamide -an opiate that does not pass the blood-brain barrier- were examined. Loperamide inhibited stimulation-induced feeding; reversal of this effect by quaternary naloxone confirmed the peripheral site of action. A low dose of morphine (1.25 mg/kg) facilitated feeding but higher doses were inhibitory. An inhibitory dose of morphine became facilitory, however, when preceded by quaternary naloxone. It therefore appears that central opioid activity promotes ingestive behavior while peripheral activity inhibits ingestion. To evaluate the function served by the central facilitory process, we exploited the relation that exists between feeding and self-stimulation elicited through a common electrode. It was found that potentiation of self-stimulation by food deprivation is blocked by naloxone. It is concluded that endogenous opioid activity may promote feeding by enhancing the reward value of food as a function of hunger

Rats were trained to press a lever to escape electrical stimulation of the nucleus reticularis gigantocellularis and to obtain stimulation of the lateral hypothalamus. Morphine sulfate and ethylketocyclazocine (EKC) both elevated the intensity of stimulation required to sustain escape at doses which did not affect self-stimulation. Parallel dose-response lines were obtained for the two opioid agonists but the effect of EKC was more resistant to naloxone antagonism. These results suggest that both mu-and chi-sub-types of opiate receptor mediate the inhibition of supraspinally-elicited aversion

Hypothalamic stimulation in rats both reduces escape from noxious hindbrain stimulation and sustains self-administration only when hindbrain stimulation is inescapable. Self-administration reflects an aversion-ameliorative action of brain stimulation and not a positive reinforcement process. The psychophysical testing used is offered as a model for establishing the analgesic properties of brain stimulation