A GIP/xenin hybrid in combination with exendin-4 improves metabolic status in db/db diabetic mice and promotes enduring antidiabetic benefits in high fat fed mice.

The current study has determined the ability of exendin-4 to augment the antidiabetic benefits of the recently characterised GIP/xenin hybrid, (DAla2)GIP/xenin-8-Gln. As such, combined activation of metabolic pathways linked to various gut derived hormones has been shown to exert complementary beneficial metabolic effects in diabetes. (DAla2)GIP/xenin-8-Gln and exendin-4 were administered twice daily to high fat fed (HFF) or db/db mice for 28 days and antidiabetic benefits assessed. Persistence of beneficial metabolic effects in HFF mice was also examined. Twice-daily injection of (DAla2)GIP/xenin-8-Gln for 28 days in HFF mice significantly reduced energy intake, body weight, circulating glucose, HbA1c and improved glucose tolerance and insulin sensitivity. Overall pancreatic islet, alpha- and beta-cell areas were reduced, with concurrent reduction in alpha- and beta-cell proliferation that was more apparent in the combined treatment group. Addition of exendin-4 to (DAla2)GIP/xenin-8-Gln therapy did not significantly improve metabolic control. Remarkably, beneficial effects were still evident 14 days following complete cessation of peptide administration. Thus, circulating glucose and insulin, HbA1c concentrations and glucose tolerance were still significantly improved when compared to control HFF mice on day 42, with minimal changes to pancreatic islet architecture. In contrast to HFF mice, combined treatment of db/db mice with (DAla2)GIP/xenin-8-Gln plus exendin-4 was required to induce beneficial effects on key metabolic parameters, which were not observed with either treatment alone. This included improvements in glucose tolerance and insulin sensitivity, but no effect on pancreatic architecture. These studies highlight the clear, and persistent, metabolic advantages of sustained activation of GLP-1 receptors, alongside concurrent activation of related GIP and xenin cell signalling pathways, in diabetes.

Peptide B targets soluble guanylyl cyclase α1 and kills prostate cancer cells.

Among androgen-regulated genes, soluble guanylyl cyclase α1 (sGCα1) is significant in promoting the survival and growth of prostate cancer cells and does so independent of nitric oxide (NO) signaling. Peptides were designed targeting sGCα1 to block its pro-cancer functions and one peptide is discussed here. Peptide B-8R killed both androgen-dependent and androgen-independent prostate cancer cells that expressed sGCα1, but not cells that do not express this gene. Peptide B-8R induced apoptosis of prostate cancer cells. Importantly, Peptide B-8R does not affect nor its cytotoxicity depend on NO signaling, despite the fact that it associates with sGCα1, which dimerizes with sGCß1 to form the sGC enzyme. Just as with a previously studied Peptide A-8R, Peptide B-8R induced elevated levels of reactive oxygen species (ROS) in prostate cancer cells, but using a ROS-sequestering agent showed that ROS was not responsible the cytotoxic activity of Peptide B-8R. Interestingly, Peptide B-8R induced elevated levels of p53 and phosphorylated p38, but neither of these changes is the cause of the peptide's cytotoxicity. Additional drugs were used to alter levels of iron levels in cells and these studies showed that Peptide B-8R activity does not depend on Ferroptosis. Thus, future work will be directed at defining the mechanism of cytotoxic action of Peptide B-8R against prostate cancer cells.

[Lymphocyte apoptosis enhancement by the synthetic peptide E in experimental ulcer].

The influence of regulatory peptide type of AFP on the course of experimental ulcer was investigated. It has been shown that activation of apoptosis enhances local necrotic inflammatory reaction, on the one hand, and enables the development of adhesions with on the other.

Increase in antinociceptive effect of [leu5]enkephalin after intrathecal administration of mixture of three peptidase inhibitors.

OBJECTIVE: Previous in vitro studies have shown that the degradation of [Leu5]enkephalin during incubation with cerebral membrane preparations is almost completely prevented by a mixture of three peptidase inhibitors such as amastatin, captopril, and phosphoramidon. The present in vivo study was performed to examine the antinociceptive effect of [Leu5]enkephalin administered intrathecally under pretreatment with these three peptidase inhibitors. METHODS: A tail-flick test was used to determine the nociceptive threshold after administration of [Leu5]enkephalin. The time-course profiles of the latency to flick the tail and the area under the time response curve were evaluated for the antinociceptive action of the drug. RESULTS: The antinociceptive effect of [Leu5]enkephalin administered intrathecally on the tail-flick test was increased more than 100-fold under i.t. pretreatment with three peptidase inhibitors. The antinociceptive effect produced by [Leu5]enkephalin in rats pretreated with any single peptidase inhibitor increased antinociception compared to that with saline. The antinociceptive potency of [Leu5]enkephalin under pretreatment with any combination of two peptidase inhibitors was smaller than that in rats pretreated with three peptidase inhibitors together. These results indicate that any residual single peptidase inactivates significant amounts of [Leu5]enkephalin. CONCLUSION: The present data, together with those of earlier studies, clearly demonstrate that amastatin-, captopril-, and phosphoramidon-sensitive enzymes play an important role in the inactivation of [Leu5]enkephalin administered intrathecally in rat.

A prodrug nanoparticle approach for the oral delivery of a hydrophilic peptide, leucine(5)-enkephalin, to the brain.

The oral use of neuropeptides to treat brain disease is currently not possible because of a combination of poor oral absorption, short plasma half-lives and the blood-brain barrier. Here we demonstrate a strategy for neuropeptide brain delivery via the (a) oral and (b) intravenous routes. The strategy is exemplified by a palmitic ester prodrug of the model drug leucine(5)-enkephalin, encapsulated within chitosan amphiphile nanoparticles. Via the oral route the nanoparticle-prodrug formulation increased the brain drug levels by 67% and significantly increased leucine(5)-enkephalin's antinociceptive activity. The nanoparticles facilitate oral absorption and the prodrug prevents plasma degradation, enabling brain delivery. Via the intravenous route, the nanoparticle-prodrug increases the peptide brain levels by 50% and confers antinociceptive activity on leucine(5)-enkephalin. The nanoparticle-prodrug enables brain delivery by stabilizing the peptide in the plasma although the chitosan amphiphile particles are not transported across the blood-brain barrier per se, and are excreted in the urine.

Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats.

Systemically active, nonpeptidic delta opioid receptor agonists have been shown to produce antidepressant and anxiolytic effects in animal models in rodents. In addition, delta agonists have been shown to increase expression of brain-derived neurotrophic factor (BDNF) mRNA, an effect of some antidepressants, which may be important for the clinical efficacy of antidepressant drugs. The present study examined whether a variety of peptidic delta agonists, DPDPE, JOM-13, a systemically active derivative of DPDPE, deltorphin II, and H-Dmt-Tic-NH-CH2-Bid could produce convulsions and antidepressant-like effects in the forced swim test. In addition, some of these compounds were examined for their influence on BDNF mRNA expression. All four agonists dose-dependently decreased immobility in the forced swim test, indicating an antidepressant-like effect. Only JOM-13 produced convulsions at doses required for antidepressant-like effects. In addition, DPDPE increased BDNF mRNA expression, as measured by in situ hybridization, in the frontal cortex. The antidepressant-like effect of the agonists in the forced swim test and the increase in BDNF mRNA expression produced by DPDPE were blocked by the delta antagonist naltrindole. Therefore, activation of the delta receptor by centrally administered peptidic agonists and intravenously administered JOM-13 produces behavioral antidepressant-like effects without producing convulsions, and some peptidic agonists can increase BDNF mRNA expression, however, not as consistently as the systemically active nonpeptidic agonists.

Effects of intrathecal BAM22 on noxious stimulus-evoked c-fos expression in the rat spinal dorsal horn.

The effects of bovine adrenal medulla 22 (BAM22), a cleaved product of proenkephalin A, were investigated on the noxious stimulus-evoked expressions of spinal c-fos-like immunoreactivity (FLI). Heat (51 degrees C) applied to the tail evoked FLI predominantly in laminae I-II of the sacral spinal cord. Intrathecal (i.t.) BAM22 at a dose of 7 nmol decreased the expressions of the heat-evoked FLI by 68%, 64% and 56% in laminae I-II, III-IV and V-VI, respectively, and the decrease pattern was comparable to that induced by i.t. morphine (10 mug). Naloxone (1 mg/kg, i.p.) significantly enhanced the heat-evoked FLI in laminae III-VI, prevented the morphine-induced inhibition, and decreased the potencies of BAM22 in laminae I-II and V-VI by 23-40%. Higher dose of naloxone (10 mg/kg, i.p.) also partially reduced the BAM22-induced suppression. Following intraplantar injection of formalin (2.5%), FLI neurons were preferentially distributed not only in laminae I-II but also in laminae III-IV and V-VI of segments L4-L5. Pretreatment with BAM22 (7 nmol, i.t.) reduced the formalin-evoked FLI neurons by 72%, 61% and 58%, in laminae I-II, III-IV and V-VI, respectively. Naloxone (1 mg/kg. i.p.) enhanced the formalin-evoked expressions of FLI in laminae III-VI and decreased the potencies of BAM22 by 22-38% in laminae I-II and V-VI. The present study provided evidence at a cellular level showing that opioid and non-opioid effects of BAM22 on nociceptive processing in acute and persistent pain models were associated with modulation of noxious stimulus-evoked activity of the spinal dorsal horn neurons.

DepoFoam technology: a vehicle for controlled delivery of protein and peptide drugs.

A major challenge in the development of sustained-release formulations for protein and peptide drugs is to achieve high drug loading sufficient for prolonged therapeutic effect coupled with a high recovery of the protein/peptide. This challenge has been successfully met in the formulation of several peptide and protein drugs using the DepoFoam, multivesicular lipid-based drug delivery system. DepoFoam technology consists of novel multivesicular liposomes characterized by their unique structure of multiple non-concentric aqueous chambers surrounded by a network of lipid membranes. The objective of this paper is to demonstrate that DepoFoam technology can be used to develop sustained-release formulations of therapeutic proteins and peptides with high loading. DepoFoam formulations of a protein such as insulin, and peptides such as leuprolide, enkephalin and octreotide have been developed and characterized. The data show that these formulations have high drug loading, high encapsulation efficiency, low content of free drug in the suspension, little chemical change in the drug caused by the formulation process, narrow particle size distribution, and spherical particle morphology. Drug release assays conducted in vitro in biological suspending media such as human plasma indicate that these formulations provide sustained release of encapsulated drug over a period from a few days to several weeks, and that the rate of release can be modulated. In vivo pharmacodynamic studies in rats also show a sustained therapeutic effect over a prolonged period. These results demonstrate that the DepoFoam system is capable of efficiently encapsulating therapeutic proteins and peptides and effectively providing controlled delivery of these biologically active macromolecules.

Use of "natural" hibernation induction triggers for myocardial protection.

BACKGROUND: Hypothermic cardioplegia provides adequate myocellular protection, yet stunning and dysfunction remain significant problems. Interestingly, the subcellular changes of hibernation parallel the altered biology of induced cardiac ischemia, but are well tolerated by hibernating mammalian myocardium. Hibernation induction trigger (HIT) from winter-hibernating animal serum induces hibernation in active animals. Hibernation induction trigger is opiate in nature and is similar to the delta 2 opioids. METHODS: To determine whether HIT could improve myocardial recovery following global ischemia, we gave 37 isolated rabbit hearts either standard cardioplegia or cardioplegia containing summer-active woodchuck, hibernating woodchuck, or black bear HIT serum or a delta 2 opioid, D-Ala2-Leu5-enkephalin, before 2 hours of global ischemia. RESULTS: Hibernation induction trigger appeared not to have an active mechanism during ischemia, as all hearts had equal recovery. In contrast, when examining for a preischemia mechanism, 23 additional rabbits received 3 days pretreatment with summer-active woodchuck or HIT hibernating woodchuck or black bear serum, or were preperfused with D-Ala2-Leu5-enkephalin or D-pen2,5-enkephalin, a-delta 1 opioid, again before 2 hours of global ischemia. Postischemic ventricular function, coronary flows, myocardial oxygen consumption, and ultrastructural preservation were all significantly improved with HIT and D-Ala2-Leu5-enkephalin pretreatment. CONCLUSION: "Natural" HIT protection is superior to standard cardioplegia alone and may have clinical application.

Central opiate mu-receptor-mediated suppression of tissue protein synthesis.

We determined the dose-dependent effects of central mu-opioid receptor stimulation on rates of tissue protein synthesis. Chronically catheterized conscious rats received an intracerebroventricular injection of [D-Ala2, N-Me-Phe4,Gly5-ol]enkephalin (DAGO, 0.5, 2, or 8 nmol/rat) or water (5 microliters) 45 min before determination of protein synthesis by the flooding dose technique. DAGO produced a significant decrease in tissue protein synthesis in liver (57%), spleen (54%), gut mucosa (36%), gut serosa (23%), kidney (48%), gastrocnemius (33%), and plantaris muscle (27%), but it did not alter rates of protein synthesis in the brain, heart, and soleus muscle. DAGO produced an acute dose-dependent respiratory depression 30 min after intracerebroventricular injection; this depression resulted in acidosis, hypoxia, and hypercapnia (pH 7.19 +/- 0.04, arterial partial O2, pressure 44.2 +/- 3.4 Torr, arterial O2 saturation 65.3 +/- 5.5%, and PCO2 66.3 +/- 4.4 Torr). Intracerebroventricular DAGO increased circulating levels of catecholamines, corticosterone, and growth hormone but did not alter those of insulin and insulin-like growth factor I. Significant positive correlations between protein synthesis and pH were observed in the tissues studied (i.e., liver protein synthesis vs. pH, P < 0.0001, r = 0.902; gastrocnemius protein synthesis vs. pH, P < 0.0001, r = 0.830). Our results indicate that mu-receptor stimulation inhibits tissue protein synthesis, and this effect appears to be secondary to respiratory depression and the resulting acidosis and/or hypoxia. Furthermore, our findings suggest differential sensitivity in tissue response to alterations in pH, hypoxia, and stress hormone elevation.

Differential effects of omega-conotoxin GVIA, nimodipine, calmidazolium and KN-62 injected intrathecally on the antinociception induced by beta-endorphin, morphine and [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin administered intracerebroventricularly in the mouse.

We previously reported that beta-endorphin and morphine administered supraspinally produce antinociception by activating different descending pain-inhibitory systems. To determine the role of spinal calcium channels, calmodulin and calcium/calmodulin-dependent protein kinase II in the production of antinociception induced by morphine, [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin (DAMGO) or beta-endorphin administered supraspinally, the effects of nimodipine (an L-type calcium channel blocker), omega-conotoxin GVIA (an N-type voltage-dependent calcium channel blocker), calmidazolium (a calmodulin antagonist) or KN-62 (a calcium/calmodulin-dependent protein kinase II inhibitor) injected intrathecally (i.t.) on the antinociception induced by morphine, DAMGO or beta-endorphin administered intracerebroventricularly (i.c.v.) were examined in the present study. Antinociception was assessed by the mouse tail-flick test. The i.t. injection of nimodipine (from 0.024 to 2.4 pmol), omega-conotoxin GVIA (from 0.0033 to 0.33 pmol), calmidazolium (from 0.0015 to 0.15 pmol) or KN-62 (from 0.0014 to 0.14 pmol) alone did not affect the basal tail-flick latencies. The i.t. pretreatment of mice with nimodipine, omega-conotoxin GVIA, calmidazolium or KN-62 dose dependently attenuated the inhibition of the tail-flick response induced by beta-endorphin administered i.c.v. However, the inhibition of the tail-flick response induced by morphine or DAMGO administered i.c.v. was not changed by i.t. pretreatment with nimodipine, omega-conotoxin GVIA, calmidazolium or KN-62. The results suggest that spinally located L- and N-type calcium channels, calmodulin and calcium/calmodulin-dependent protein kinase II may be involved in the modulation of antinociception induced by beta-endorphin, but not morphine and DAMGO, administered supraspinally.

Chronic intracerebroventricular administration of beta-endorphin augments natural killer cell cytotoxicity in rats.

We have studied the effect of chronic intracerebroventricular (i.c.v.) infusion of different opioid peptides on natural killer (NK) cell mediated cytotoxicity in vivo in the spontaneously hypertensive rat (SHR). The in vivo NK cell activity was measured as the clearance of 51Cr-labelled YAC-l lymphoma cells from the lung tissues. Further, the phenotype of lymphocytes in spleen and peripheral blood was analysed by flow cytometry (FACS). All opioid drugs were administered i.c.v. for 6 days with osmotic minipumps releasing 1.0 microliter/h. beta-Endorphin (10 or 20 micrograms/rat per day) significantly increased NK cell cytotoxicity in vivo. The opioid receptor antagonist naloxone (10 mg/kg, i.p.) given immediately before the injection of YAC-lymphoma cells, completely abolished the effects of i.c.v. administered beta-endorphin. Corresponding doses of beta-endorphin administered subcutaneously (s.c.) with minipumps for 6 days did not significantly affect NK cell cytotoxicity. Neither Leu- or Met-enkephalin (20 micrograms/rat per day) nor dynorphin (20 micrograms/rat per day) administered i.c.v. had any significant effects on NK cell activity. In beta-endorphin treated SHR, the percentage of cells with NK cell phenotype (OX52+/CD5-) in peripheral blood was not significantly different from that of controls, while the percentage of cells with T cell phenotype (CD5+/OX52-) was significantly decreased. The percentage of splenic NK cells (OX52+/CD5-) and T cells (CD5+/OX52-) was also unchanged by beta-endorphin treatment i.c.v. These results suggest that of the opioid peptides administered i.c.v., only beta-endorphin augments in vivo NK cell mediated cytotoxicity. We thus conclude that these effects most probably are centrally and opioid receptor mediated effects, since beta-endorphin in the same dose administered peripherally does not influence in vivo NK cell cytotoxicity.

Inhibition of noxious stimulus-evoked pain behaviors and neuronal fos-like immunoreactivity in the spinal cord of the rat by supraspinal morphine.

In previous studies, we reported that supraspinally administered DAMGO, a mu-opioid agonist, produces a dose-related, naloxone-reversible inhibition of formalin-evoked pain behaviors and spinal cord Fos-like immunoreactivity (FLI) in the rat spinal cord. Although these results support the hypothesis that activation of supraspinal mu-opioid receptors produces antinociception by increasing the activity of bulbospinal inhibitory pathways, other studies suggest that supraspinal morphine decreases rather than increases descending inhibitory control. In the present study, we specifically examined the effect of intracerebroventricular (i.c.v.) injection of morphine in the rat. Supraspinal morphine produced a dose-related, naloxone-reversible inhibition of both formalin-evoked behaviors nd spinal cord FLI. Although the magnitude of the antinociception produced by i.c.v. morphine in the formalin test was significantly correlated with the numbers of FLI neurons in the spinal cord, the lowest dose of i.c.v. morphine tested (0.70 nmol) produced a significant reduction of FLI in the superficial laminae without producing behavioral antinociception, which is consistent with our hypothesis that noxious stimulus-evoked Fos expression in the superficial laminae is a poor predictor of the magnitude of pain behavior. These data support the hypothesis that the antinociceptive effects of supraspinally administered morphine result from an increase in descending inhibitory control.

[The analgesic action of new enkephalin analogs]. / O boleutoliaiushchem deistvii novykh analogov énkefalinov.

The enkephalin analogue peptide IKB-901 containing epsilon-ACA and cysteine with the modified S-end shows an analgetic activity in rats (1 micron, intrathecally and 5 mg/kg intravenously) and in cats (0.35 and 0.7 mg/kg intravenously). Naloxone (0.1 mg/kg) prevents the analgetic effect of peptide. The coadministration of the peptide and the enkephalinase inhibitor D-phenylalanine (0.35 and 10 mg/kg, respectively) enhances analgesia and displays an antihypertensive effect in nociceptive stimulation.

Evidence that nor-binaltorphimine can function as an antagonist at multiple opioid receptor subtypes.

This study examined the influence of acute and repeated administration of the kappa-opioid receptor antagonist, nor-binaltorphimine, upon opioid-induced antinociception as measured by the tail-pressure test. A single intracerebroventricular (i.c.v.) injection of nor-binaltorphimine (30 micrograms) administered 1, 10 or 30 days prior to algesiometric testing prevented the analgesic effect of the kappa-opioid receptor agonist, (5 alpha, 7 alpha, 8 beta)-(-)-N- methyl-N-(7-(1-pyrrolidinyl)-1-oxaspiro(4,5)dec-8-yl)benzenacet amide (U69593). The analgesic effect of the mu-opioid receptor agonist, [D-Ala2,N-methyl-Phe4,Gly5-ol]enkephalin (DAMGO), and the delta-opioid receptor agonist, [D-Pen2,D-Pen5]enkephalin (DPDPE), was not modified. In contrast, when nor-binaltorphimine was administered repeatedly (twice daily i.c.v. administration of 30 micrograms nor-binaltorphimine for 10 days), the analgesic effect of DAMGO, DPDPE as well as U69593 was abolished. In the case of mu- and delta-opioid receptor agonists, this abolition was apparent when testing occurred 1 or 2, but not 5 days after termination of nor-binaltorphimine treatment. This treatment regimen also resulted in a long-lasting antagonism (e.g. 20 days) of U69593-induced analgesia. These data show that, depending on the treatment regimen employed, nor-binaltorphimine can function as a selective kappa-opioid receptor antagonist, or as an antagonist at multiple opioid receptor subtypes. Further, they demonstrate that nor-binaltorphimine functions as a long-lasting kappa-opioid receptor antagonist in vivo.

Effects of mu, delta and kappa opioid antagonists on the depression of a C-fiber reflex by intrathecal morphine and DAGO in the rat.

The roles of mu, delta and kappa opioid receptor subtypes in spinal morphine-induced antinociception were investigated. A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. Recruitment curves were built by varying the stimulus intensity from 0 to 7x threshold and temporal evolutions were studied by using a constant level of stimulus intensity (3x threshold). Intrathecal administration of naloxone, Cys2-Tyr3-Orn5-Pen7 amide (mu opioid receptor antagonist) and nor-binaltorphimine (nor-BNI, a kappa opioid receptor antagonist) completely antagonized the depression of the C-fiber reflex induced by 4 nmol of intrathecal morphine, whereas the antagonistic effect of naltrindole (a delta receptor antagonist) was limited, with a ceiling effect of 56%. The AD50 were 12 pmol and 1, 4.3 and 39 nmol for Cys2-Tyr3-Orn5-Pen7 amide, naloxone, nor-BNI and naltrindole, respectively. When injected alone, only naltrindole induced a short-duration depressive effect. Intrathecal administration of DAGO resulted in a depressive effect on the C-fiber reflex in a dose-dependent manner; for a stimulus intensity of 3x threshold, the ED50 was 9 pmol. DAGO was found to be 60 times more potent than morphine. Interestingly, nor-BNI, at doses which reversed the blockade of the C-fiber reflex by morphine, also reversed the effects of an equipotent dose of DAGO, which suggested an action on a mu receptor subtype.

Cyclic AMP mediates mu and delta, but not kappa opioid analgesia in the spinal cord of the rat.

Intrathecal (i.t.) injection of the membrane-permeable cyclic AMP (cAMP) analogue dibutyryl-cyclic AMP (Bt2cAMP) in 3 successive doses of 12.5, 12.5 and 25 ug in rats was very effective in reversing the antinociceptive effects produced by mu agonist morphine or delta agonist DPDPE, but not that by kappa agonist dynorphin A-(1-13). cAMP content of the spinal cord was significantly decreased by morphine, but not by dynorphin A-(1-13). The results imply that a decrease in spinal cAMP content may be important for the antinociceptive effect elicited by mu and delta, but not kappa opioid receptor agonists.

Mu-, delta-, and kappa-opioid receptor agonists selectively modulate sexual behaviors in the female rat: differential dependence on progesterone.

Previous studies suggested that opioid receptor agonists infused into the lateral ventricles can inhibit (through mu receptors) or facilitate (through delta receptors) the lordosis behavior of ovariectomized (OVX) rats treated with estrogen and a low dose of progesterone. The present study investigated the behavioral and hormonal specificity of those effects using more selective opioid receptor agonists. Sexually experienced OVX rats were implanted stereotaxically with guide cannulae aimed at the right lateral ventricle. One group of rats was treated with estradiol benzoate (EB, 10 micrograms) 48 hr and progesterone (P, 250 micrograms) 4 hr before testing, whereas the other group was treated with EB alone. Rats were infused with different doses of the selective mu-receptor agonist DAMGO, the selective delta-receptor agonist DPDPE, or the selective kappa-receptor agonist U50-488. The females were placed with a sexually vigorous male in a bilevel chamber (Mendelson and Gorzalka, 1987) for three tests of sexual behavior, beginning 15, 30, and 60 min after each infusion. DAMGO reduced lordosis quotients and magnitudes significantly in rats treated with EB and P, but not in rats treated with EB alone. In contrast, DPDPE and U50-488H increased lordosis quotients and magnitudes significantly in both steroid-treatment groups. Surprisingly, measures of proceptivity, rejection responses, and level changes were not affected significantly by mu or kappa agonists, although proceptivity and rejection responses were affected by DPDPE treatment. These results suggest that the effects of lateral ventricular infusions of opioid receptor agonists on the sexual behavior of female rats are relatively specific to lordosis behavior. Moreover, the facilitation of lordosis behavior by delta- or kappa-receptor agonists is independent of progesterone treatment, whereas the inhibitory effect of mu-receptor agonists on lordosis behavior may require the presence of progesterone.

Inhibition of spinal opioid analgesia by supraspinal administration of selective opioid antagonists.

The effect of intracerebroventricular administration of a selective mu- (CTOP) or delta- (ICI 174,864) opioid receptor antagonist on the antinociceptive effects produced by intrathecal administration of selective mu- (DAMGO), delta- (DPDPE) and kappa- (U50-488H) opioid receptor agonists was evaluated using the Randall-Selitto paw-withdrawal test, in the rat. While the intracerebroventricular administration of CTOP or ICI 174,864, alone, had no effect on nociceptive thresholds, intracerebroventricular administration of CTOP and ICI 174,864 produced marked antagonism of the antinociceptive effects of intrathecal DAMGO. The antinociceptive effects of intrathecal administration of DPDPE or U50,488H were not antagonized by intracerebroventricular administration of CTOP or ICI 174,864. These data suggest that, in the rat, along with the established descending antinociceptive pathways, there is an ascending antinociceptive control mechanism projecting from the spinal cord to the brainstem. The ascending antinociceptive control involves mu- and delta-opioid agonism at supraspinal sites and appears to be mediated selectively by mu-, but not by delta- or kappa-opioid agonism at the spinal level.