Butorphanol tartrate induces feeding in rats

Peripheral administration of butorphanol tartrate markedly enhanced feeding from 0800 to 1400 hours when compared with vehicle controls. Butorphanol tartrate feeding was not antagonized by doses of naloxone as high as 10 mg/kg. These data support the concept that the kappa or sigma opiate receptors are involved in feeding behavior.It is well recognized that the endogenous opiates play a role in the central regulation of appetite (1, 2, 3, 4). Numerous studies have shown that The endogenous opioid peptides and morphine can initiate feeding under various conditions (5–12) whereas the opiate antagonist, naloxine can reduce food consumption (13–20). Recently, the endogenous opiod peptide, dynorphin, has been reported to enhance food intake (12–25).Much evidence has been accumulated indicating that a number of opiate receptors are present in the brain, each one having a high affinity for a specific endogenous opioid peptide (26, 27). Both the cyclazocine related compounds (28) and the feeding enhancer, dynorphin (29–32), have been reported to be specific kappa receptor agonists. In the present study, we report on the effect of the morphinan congener, butorphanol tartrate (33), on ingestive behaviour.     

Effect of opioid agonist-antagonist interaction on morphine dependence in rats

Morphine dependence was induced by treatment with morphine-admixed food (0.25mg/g of food) for 7 days. Withdrawal was precipitated by injecting naloxone (0.5mg/kg, s.c.). Rats treated with morphine exhibited body weight loss upon the naloxone injection. When morphine-dependent rats were injected subcutaneously with morphine, codeine, meperidine and pentazocine 30 min before the naloxone injection, these drugs significantly suppressed the naloxone-precipitated loss of body weight in a dose-dependent manner. However, body weight loss induced through coadministration of naloxone and Mr-2266 BS were not suppressed by morphine pretreatment. These results suggest that opioids protect against naloxone-precipitated loss of body weight, and that mu and kappa opiate receptors play an important role in the protection against naloxone-precipitated withdrawal.     

Ketazocines and morphine: effects on gastrointestinal transit after central and peripheral administration

The mu agonist, morphine, and the prototype kappa agonists, ketocyclazocine and ethylketocyclazocine (EK), were studied for their effects on gastrointestinal transit. Following s.c. administration, both morphine (0.3-3 mg/kg) and ketocyclazocine (0.3-10 mg/kg) antagonized transit of an opaque marker through the small intestines of mice. Morphine (0.1-1 microgram) was also effective after intracerebroventricular (icv) administration in mice whereas ketocyclazocine (0.3-30 micrograms) was not. Similarly, while both morphine (0.3-5 mg/kg) and EK (0.6-10 mg/kg) slowed transit after s.c. injection to rats, only morphine (1-10 micrograms), but not EK (0.3-300 micrograms), was active following icv administration. Icv infusion of the mu benzomorphan, phenazocine (10-100 micrograms), slowed transit in a dose-related manner. These results indicate that there may be an anatomically distinct distribution of receptors for benzomorphan kappa agonists in both the mouse and rat, with these opiate receptors not being located near the lateral cerebral ventricles. The difference in efficacy between morphine and ketazocines in slowing gastrointestinal transit after icv administration to rodents suggests that (a) inactivity in this endpoint is a characteristic of benzomorphan kappa compounds and (b) the model may serve as a useful screen when establishing in vivo profiles of kappa agonists in mice and rats.     

Effects of the opiate antagonists diprenorphine and naloxone and of selected opiate agonists on feeding behavior in guinea pigs

Opiate-sensitive feeding behavior has now been demonstrated in a number of species. We sought information on which opioid receptors might be involved in the observed feeding behaviors. Guinea pigs are known to have higher concentrations of the opioid kappa receptor than any other laboratory animal, so we compared the feeding suppressive potency of the general opiate antagonist, diprenorphine to that of the relatively more mu-specific antagonist, naloxone in that species. We found that diprenorphine was over twenty times more effective than naloxone in suppressing feeding in guinea pigs, suggesting the importance of receptors other than mu in feeding initiation in the guinea pig. Confirmatory evidence for the role of kappa receptors was sought, but not found, in comparisons of the effectiveness of different types of opiate agonists in promoting feeding in these animals. These agonists suppressed, rather than stimulated feeding. We conclude that no feeding stimulatory effects of opiates can be demonstrated in guinea pigs. This observation may indicate that opioids play little role in the natural regulation of feeding in this species or that opioids result in prolonged sedation during which the animals fail to eat. The greater feeding suppressive potency of diprenorphine, a general opiate antagonist, versus naloxone, a mu-preferential antagonist, indicates that to whatever extent opiates are involved in guinea pig feeding, the opiate effect is probably not a mu receptor effect.     

Differential opiate influences on food hoarding and intake in the deer mouse, Peromyscus maniculatus

The feeding behavior of the deer mouse, Peromyscus maniculatus, includes food hoarding as well as ingestion. In this animal the mu opiate agonist, morphine, and the kappa opiate agonist, U-50, 488H, selectively stimulate food hoarding and ingestion, respectively. This suggests that mu and kappa opiate systems may differentially mediate primary components of natural feeding behavior.     

Opioid involvement in the control of feeding in an insect, the American cockroach

Administration of the kappa opiate agonist, U-50,488H (0.10-10 mg/kg), produced over three hours a significant dose-dependent increase in the ingestive responses of free feeding American cockroaches, Periplaneta americana. These effects could be decreased by the opiate antagonist, naloxone (1.0 mg/kg), with naloxone by itself blocking the augmented feeding responses of food-deprived cockroaches. The mu opiate agonist, morphine (1.0-20 mg/kg) caused a significant dose-dependent and naloxone-reversible increase in the locomotory activity of cockroaches. These results suggest that opioid systems may be involved in the control of the feeding in cockroaches in a manner analogous to that proposed for vertebrates.     

Catatonic or hypotonic immobility induced in mice by intracerebroventricular injection of mu or kappa opioid receptor agonists as well as enkephalins or inhibitors of their degradation

The intracerebroventricular injections in mice of the mu receptor agonists morphine and fentanyl induced an immobility state (the animals staying motionless with the head down on a 45° inclined plane) which was apparently hypertonic (catatonia ?) or at least enabled them to remain hanging on a horizontal wire with their forepaws. In similar conditions, injections of the kappa receptor agonists ketocyclazocine and bremazocine induced an immobility state which was hypotonic, in contrast with the preceding one. In a similar way to the mu agonists, Met-enkephalin or Leu-enkephalin injected i.c.v. in association with the inhibitor of enkephalinase thiorphan induced an apparently hypertonic immobility which was easily antagonized by naloxone. The association of thiorphan with bestatin ( an inhibitor of aminopeptidases involved in enkephalins inactivation ) produced similar results. In contrast, the hypotonic immobility induced by the kappa receptor agonists required relatively high doses of naloxone to be antagonized. The opiate antagonist MR 2266 antagonized equipotent doses of all the above mentioned agents with a similar efficacy. From these data it is suggested that enkephalins could induce an apparently tonic immobility by stimulating mu receptors and that endogenous enkephalins could be involved in a tonic mediation modulating the locomotor activity or regulating the muscular tone.     

Orally administered kappa as well as mu opiate agonists delay gastrointestinal transit time in the guinea pig

When an orally administered opiate agonist is systemically bioavailable, the relative activity of that opioid in delaying gastrointestinal transit (GIT) depends on its relative action at central and peripheral sites. This in turn depends on the density of opioid receptor specific subtypes at those sites of action in the species under study. In rats the kappa selective agonist U-50,488H has no effect on GIT. We have found that this same agonist is equipotent to mu agonists morphine and 1-methadone in delaying the orocecal transit of a charcoal meal when administered orally to guinea pigs. Thus, both kappa as well as mu receptor subtypes are involved in the mechanisms of opiate induced slowing of GIT in the guinea pig in contrast to the rat. Interspecies differences must be considered when determining the contribution of opiate receptor subtypes to the mechanisms of opiate-induced constipation.     

Feeding induced by opiates injected into the paraventricular hypothalamus

Injection of morphine or d-ala-2-met-5-enkephalinamide (DALA) into the paraventricular nucleus of the hypothalamus (PVN) produced a dose dependent increase in feeding in rats. DALA increased feeding within 45 minutes; morphine within 90 minutes. Naloxone injected into the PVN diminished the effect. DALA increased water intake only when food was available, suggesting the primary effect was on feeding. In summary, an enkephalin analogue induced feeding, and an opiate receptor blocker attenuated it; therefore the PVN may contain opiate receptors that facilitate feeding.     

ACTH-(1-24) and alpha-MSH antagonize feeding behavior stimulated by kappa opiate agonists

ACTH-(1-24) and alpha-MSH, intracerebroventricularly (ICV) injected at the doses of 4 and 10 micrograms/animal, respectively, markedly inhibited spontaneous feeding in adult Sprague-Dawley rats, the effect remaining significant for 6-9 hours. At these same doses, ACTH-(1-24) and alpha-MSH abolished the feeding-stimulatory effect of the kappa opiate receptor agonist pentazocine, intraperitoneally (IP) injected at the dose of 10 mg/kg. The same antagonism was obtained by ICV injection of ACTH-(1-24) into rats IP treated with other kappa opiate agonists, bremazocine and tifluadom, at the doses of 1 and 5 mg/kg, respectively. These data suggest that melanocortin peptides play an inhibitory role in the complex regulation of food intake, and further support and extend the hypothesis of a melanocortin-opioid homeostatic system, its two neuropeptide components usually having opposite, mutually-balancing effects.     

Opioid pharmacology in the rat hippocampal slice

The ability of several opioids in potentiating the synaptic activation of CA1 pyramidal cells in the rat hippocampal slice were compared. Morphine and the opioid peptides, (D-ala2, D-leu5)-enkephalin (DADL), morphiceptin, beta-endorphin, and Tyr-D-Ser-Gly-Phe-Leu-Thr (DSThr) caused a concentration-dependent, naloxone-reversible shift to the left in the input-output (IO) curve constructed by plotting the population spike as a function of the field EPSP. These opioids then produced an increase in the size of the population spike while leaving the EPSP unaffected. In contrast, the kappa agonist prototype, ethylketazocine, had no effect on the IO curve when perfused in concentrations up to 10 microM. The rank order of potency for the opioids in the CA1 region of the hippocampus was DADL greater than DSThr greater than beta-endorphin greater than morphiceptin greater than morphine much greater than ethylketazocine. Thus, opioids that are more specific for delta opiate receptors were the most potent and mu receptor agonists, the least potent in this action. Taken together with previous studies suggesting that morphine and DADL may interact with a common opiate receptor in the CA1 region, the results are consistent with the notion that these epileptiform effects may be primarily mediated by delta opiate receptors in this area although the potency of morphiceptin indicates that mu receptors play some role in this effect.     

Slugs and snails and opiate tales: opioids and feeding behavior in invertebrates

There is accumulating evidence that opioid systems are involved in the regulation of fundamental behavioral and physiological processes in invertebrates. Feeding is a basic physiological function that is essential for maintaining homeostasis. Results of studies examining the feeding responses of molluscs and arthropods treated with various opiate agonists and antagonists indicate that delta, kappa, mu, and possibly sigma opioid systems differentially and selectively mediate the components of their natural feeding behavior. Moreover, it appears that at an early evolutionary stage the mu and kappa systems have developed to selectively affect the components of feeding behavior associated with the acquisition and ingestion of food. In addition, evidence suggests that neuropeptides that have been proposed as possible endogenous antagonists of opioid-mediated feeding in mammals may also be involved in the control of feeding in invertebrates. This indicates that there may be an interplay of opioid agonists and antagonists in the regulation of feeding and satiation in invertebrates analogous to that proposed for vertebrates. Moreover, these findings indicate that opioid influences on feeding have been conserved through evolution.     

Long-term enhancement of morphine hypalgesia as a result of periodic blockade of opiate receptors using naloxone

A significant enhancement of the analgetic effect of morphine (6 mg/kg, subcutaneously; tail withdrawal reflex at 60 degrees C) was observed in rats 3-4 hours after single naloxone (1 mg/kg) administration. Periodical naloxone injection (0.5 mg/kg, subcutaneously, 3 times per day at 3.5-hour intervals for 3 days) led to a prominent and long-term (testing on the 20th and 105th hour after the last naloxone administration) enhancement of morphine analgesia (2.6 mg/kg subcutaneously) and insignificant inhibition of stress analgesia during two-hour immobilization of animals. These modifications of morphine and stress analgetic effects are considered a result of adaptive changes of opiate receptors after their blockade.     

Enhancement of opiate-induced depressions in serum luteinizing hormone levels by the prior administration of naloxone in the male rat

The effects of naloxone pretreatment on opiate agonist-induced depressions in serum luteinizing hormone (LH) levels were examined in male rats. Our results demonstrated a pronounced enhancement of morphine's actions 6 hours after the administration of naloxone (0.5 mg/kg). This effect was characterized by a 10 fold reduction in the ED50 (1.26 mg/kg versus 0.13 mg/kg in saline- and naloxone-pretreated rats, respectively) and much greater depressions in serum LH levels at each dose of morphine. The actions of naloxone were not confined to morphine, since similar increased potencies were found for opioid agonists with selectivity for a variety of opioid receptor subtypes. Because naloxone did not alter the uptake of subsequently administered morphine into brain, our results cannot be explained on the basis of an increased availability of the agonist. Rather, it appears that naloxone pretreatment induces a change in the sensitivity of those receptors involved in the effects of opioid agonists on LH.     

Chronic, but not acute, administration of morphine alters antiopiate (Tyr-MIF-1) binding sites in rat brain

Opiate addiction could involve a change in the binding of endogenous antiopiates. A candidate for such a role is Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), a brain peptide that can antagonize exogenous and endogenous opiates and bind to opiate receptors. Its primary action, however, may be through its own binding site in brain, which we now report is altered by chronic administration of morphine. Rats given morphine pellets had reduced binding of both iodinated and tritiated Tyr-MIF-1 on day 5, when substantial tolerance is evident. In contrast, mu and delta opiate receptors were increased. Acute injection of an analgesic dose of morphine did not reduce Tyr-MIF-1 binding, indicating that chronic administration is required for the change. These findings open new approaches to the study of addiction by focusing on antiopiate activity.     

Mu-opiate binding and morphine antagonism by octapeptide analogs of somatostatin

A series of cyclic conformationally restrained octapeptide analogs of somatostatin were examined for their ability to inhibit the binding of tritiated mu, kappa, and delta opiate receptor ligands. Several of these substances were found to have high affinity for mu opiate receptors while having very low affinity for both kappa and delta receptors. Previous suggestions that somatostatin analogs exhibit opiate antagonist activity led to a study of the ability of the two most potent compounds to inhibit morphine analgesia in rats after intracerebroventricular injection. One of the compounds significantly antagonized morphine analgesia although the other displayed severe toxicity. These two compounds differed in that the very toxic compound had previously been found to possess significant somatostatin activity. It thus appears that the structural requirements for toxicity and somatostatin activity can be differentiated from those for opiate activity.     

Receptor-related interactions of opiates with PGE-induced adenylate cyclase in brain

The inhibition by opiates of the PGE2-induced formation of cAMP in slices from rat brain striatum was investigated. A maximal, 3.5-fold increase over the basal level of cAMP was obtained with an EC50 for PGE2 of 3 microM. Opiate agonists of both mu and kappa type were inhibitory. The IC50 values for morphine, levorphanol and ethylketocyclazocine (EKC) were 110 nM, 80 nM and 25 nM, respectively. These values were similar to the potencies of the compounds in displacing stereospecifically bound 3H-etorphine in rat brain membranes. As evidenced by the inactivity of dextrorphan, the inhibition of PGE2-dependent cAMP formation was stereospecific. Also ineffective were the opiate antagonists naloxone, naltrexone and MR 2266. These compounds did, however, reverse the inhibition by agonists, displaying thereby selectivity toward the putative mu and kappa opiates. Thus, the inhibition by morphine was antagonized to a greater degree by naloxone than by MR 2266, and the action of EKC was blocked more effectively by MR 2266 relative to naloxone.     

Prejunctional effects of opioids in the perfused mesentery of the rat and rabbit: interactions with alpha 2-adrenoceptors.

Prejunctional effects of opioids were examined in the perfused mesentery of two species: the rat and rabbit. Use of agonists selective for subtypes of mu, delta, and kappa opioid receptors produced no effect on contractile responses to adrenergic nerve stimulation in the rat perfused mesentery, except for small effects of the kappa agonist EKC, which may be non specific. In contrast, mu, delta and kappa receptors appear to be present in the rabbit. The mu selective agonist, DAMGO, kappa agonist, ethylketocyclazocine, and delta agonists, DPDPE and [Leu5]-enkephalin, all produced significant inhibition of contractile responses to transmural nerve stimulation. The inhibitory effect was greatest for ethylketocyclazocine. To test the possibility that prejunctional activation of alpha 2 adrenoceptors with endogenous norepinephrine might decrease the activity of prejunctional opioid receptors in the rabbit, inhibitory effects of delta and kappa selective agonists were tested in the presence of 10(-7) M yohimbine. Inhibitory responses of the kappa selective agonist ethylketocyclazocine were enhanced, while that of delta selective agonists [Leu5]-enkephalin and DPDPE remained unchanged when yohimbine was present. Thus, the effects of opioids vary and depend on the tissue and receptor subtypes they act upon. Furthermore, the enhanced inhibitory effect of opioid receptor activation in the presence of yohimbine is not found for all opioid receptors.     

Effect of the opiate antagonist naloxone on the electrical activity of identified neurons in the edible snail

The opiate antagonist naloxone modifies the electric activity of some identified neurons of the Helix lucorum which have not been preliminary exposed to the effect of exogenous opioids. Some neurons are excited while others are inhibited by naloxone, and in both cases the reaction may have both a short and long latent period. The reactions depend on naloxone dose and become less expressed or are blocked when naloxone is administered together with the agonists of opiate receptor (morphine, D-Ala2, D-Leu5-enkephalin, bremazocine and beta-endorphin). Opioids alone do not produce any effect on neurons. The effect of naloxone on neurons is assumed to be a result of the elimination by the opiate antagonist of the tonic effect of endogenous opioids by their replacing on opiate receptors which are constantly stimulated by endogenous ligands.     

Chronic administration of clomipramine inhibits morphine hot plate analgesia

Clomipramine, chronically administered in mice, for 3 days, inhibits partially but significantly morphine analgesia in the hot plate test, when used at dose of 10 mg/kg/day, i.p.; 2.5 and 5 mg/kg/day were ineffective. Neither higher doses (20 and 40 mg/kg/day) nor longer duration of pretreatment (8 and 16 days) modified the intensity of this inhibition. Reduction in morphine analgesia was obtained after a 24h delay between the last injection of clomipramine and that of morphine (30 min before testing), while clomipramine did not induce any antinociceptive effect and clomipramine and desmethylclomipramine plasma and brain levels were low or undetectable. These results provide new evidence for the interaction between clomipramine and the endogenous opiate system. A pharmacokinetic interaction between clomipramine and morphine was excluded; involvement of change in opiate and 5 HT2 receptors by chronic administration of clomipramine is discussed.