beta-funaltrexamine and binaltorphimine

This study was performed to clarify mechanisms underlying pentazocine-induced ventilatory depression and antinociception. Spontaneous ventilation and hind leg withdrawal response against nociceptive thermal stimulation were simultaneously recorded in anesthetized rats. Pentazocine decreased minute volume resulting from depression of the ventilatory rate and tracheal airflow, and prolonged the latency of withdrawal response. Pre-treatment of β-funaltorexamine, but not nor-binaltorphimine, significantly attenuated pentazocine-induced ventilatory depression, while either antagonist weakened its analgesic potency. Comparing with effects of fentanyl and U50488, the present results suggest that ventilatory depression induced by pentazocine is mediated by mainly μ receptors and analgesia by both μ and κ receptors.

Topics: Analgesics; Anesthesia; Animals; Male; Naltrexone; Pentazocine; Rats, Wistar; Receptors, Opioid, kappa; Receptors, Opioid, mu; Respiratory Insufficiency

Melanin-concentrating hormone (MCH) exerts an orexigenic effect that resembles that of opioids, suggesting that the MCH and opioid systems could interact in controlling the food intake behavior. Three series of experiments were conducted in male Wistar rats: 1) to test the ability of the κ-, μ-, and δ-opioid receptor antagonists binaltorphimine (nor-BNI-κ), β-funaltrexamine (β-FNA-μ), and naltrindole (NTI-δ), respectively, to block the stimulating effects of MCH on food intake; 2) to verify the ability of MCH to induce a positive hedonic response to a sweet stimulus when injected into the nucleus accumbens shell (NAcSh) or right lateral ventricle (LV) of the brain; and 3) to assess the ability of nor-BNI, β-FNA, and NTI to block the effects of MCH on the hedonic response to a sweet stimulus. Nor-BNI, NTI (0, 10 and 40 nmol), and β-FNA (0, 10 and 50 nmol) were administered into the LV prior to injecting MCH (2.0 nmol). To assess the hedonic response, rats were implanted with an intraoral cannula allowing for the infusion of a sweet solution into the oral cavity. Food intake was assessed in sated rats during the first 3 h following the MCH or vehicle (i.e., artificial cerebrospinal fluid) injection. The hedonic response to a sweet stimulus was assessed by examining facial mimics, following the intraoral administration of a sucrose solution. Blockade of each of the three opioid receptors by selective antagonists prevented MCH-induced feeding. Furthermore, MCH-injections into the NAcSh and right LV resulted in enhanced hedonic responses. Finally, antagonism of the three opioid receptors blunted the LV-injected, MCH-induced, facial-liking expressions in response to an intraoral sweet stimulus. Overall, the present study provides evidence to link the MCH and opioid systems in the food intake behavior.

Topics: Analgesics, Opioid; Animals; Behavior, Animal; Eating; Hypothalamic Hormones; Injections, Intraventricular; Male; Melanins; Models, Animal; Naltrexone; Narcotic Antagonists; Pituitary Hormones; Rats; Rats, Wistar; Receptors, Opioid; Sucrose; Taste

Previous studies have shown that mu (mu) and kappa (kappa) opioid antagonists inhibit suckling-induced prolactin release. Prolactin responses elicited by pup suckling or opioid administration are mediated, at least in part, by suppression of dopamine (DA) release from tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We examined the effects of the mu opiate receptor antagonist, beta-funaltrexamine (beta-FNA), and the kappa opiate receptor antagonist, nor-binaltorphimine (nor-BNI) on the activity of TIDA neurons in lactating rats. TIDA neuronal activity was determined by measuring DOPA accumulation in the caudate putamen (CP) and median eminence (ME). The effects of opioid antagonist treatment were determined in pup-deprived (low circulating prolactin levels) or pup-suckled rats (high circulating prolactin levels). The accumulation of 5-hydroxytryptophan (5-HTP) in the medial preoptic area (MPOA), the anterior hypothalamus (AH) and the median eminence (ME) was quantified as an index of serotonergic activity in the same animals for comparative purposes. In vehicle treated rats, suckling caused a significant and selective decrease in DOPA accumulation in the ME. beta-FNA (5 micrograms, i.c.v.) pretreatment significantly increased DOPA accumulation in the ME of pup-deprived and pup-suckled rats. beta-FNA pretreatment also prevented the suckling-induced suppression of DOPA accumulation in the ME. In contrast to the actions of beta-FNA, pretreatment with nor-BNI (8 micrograms, i.c.v.) did not significantly affect the activity of the TIDA neurons in pup-deprived or pup-suckled rats. Suckling alone did not alter 5-HTP accumulation in any of the brain regions examined, and neither opioid antagonist had appreciable effects on 5-HTP accumulation. These results demonstrate that the EOP tonically inhibit the TIDA neurons in both pup-deprived and pup-suckled, post-partum female rats by acting through the mu, but not the kappa, opiate receptor subtype. Furthermore, the suckling-induced inhibition of TIDA neurons is also mediated through the EOP acting at mu, but not kappa opioid receptors.

Topics: 5-Hydroxytryptophan; Animals; Caudate Nucleus; Dihydroxyphenylalanine; Dopamine; Female; Hypothalamus, Anterior; Lactation; Male; Median Eminence; Naltrexone; Neurons; Preoptic Area; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin; Sucking Behavior

The present study examined the opioid receptors involved in the antitussive effect of dihydroetorphine in mice. Dihydroetorphine suppressed coughs dose dependently at doses between 0.1-1 micrograms/kg i.p. Blockade of mu-opioid receptors by pretreatment with beta-funaltrexamine significantly reduced the antitussive effect of dihydroetorphine. Furthermore, the antitussive effect of dihydroetorphine was also antagonized by nor-binaltorphimine, a kappa-opioid receptor antagonist. However, pretreatment with naltrindole, a delta-opioid receptor antagonist, did not affect the antitussive effect of dihydroetorphine. These results indicate that the antitussive effect of dihydroetorphine is mediated by the activation of mu-opioid receptors and of kappa-opioid receptors, but not delta-opioid receptors.

Topics: Alkylating Agents; Animals; Antitussive Agents; Cough; Dose-Response Relationship, Drug; Etorphine; Injections, Intraperitoneal; Male; Mice; Naltrexone; Narcotic Antagonists; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu

Tail-pinch feeding (TPF) in rats is decreased following general (naltrexone, NTX) and mu (Cys2-Tyr3-Orn5-Pen7-amide, CTOP) opioid antagonists, but not following kappa (nor-binaltorphamine. Nor-BNI) or delta (naltrindole, NTI) opioid antagonists. Because multiple mu (mu1 and mu2) and delta (delta 1 and delta 2) opioid receptor subtypes have been characterized, the present study evaluated whether TPF was differentially altered following ICV administration of general (NTX), mu (beta-funaltrexamine, B-FNA), mu1 (naloxonazine, NAZ), kappa (Nor-BNI), delta 1 ([D-Ala2, Leu5, Cys6]-enkephalin, DALCE) and delta 2 (NTI) opioid antagonists. Like the reversible mu antagonist CTOP, the irreversible mu antagonist B-FNA significantly and dose-dependently (1-20 micrograms) reduced TPF by up to 28%. In contrast, whereas NAZ (50 micrograms) reduced TPF by 32%, this effect was highly variable and failed to achieve significance. Neither NTX (5-10 mg/kg, SC), Nor-BNI (20 micrograms), DALCE (40 micrograms) nor NTI (20 micrograms) significantly altered TPF, suggesting that kappa, delta 1 and delta 2 opioid receptor subtypes were not involved. Because no antagonist altered the duration of food contact during tail pinch, it appears that the opioid effect modulates ingestive rather than activational mechanisms. The reliable inhibition of TPF by B-FNA (mu1 and mu2), together with the variable effect of naloxonazine (mu1), appears to implicate both mu binding sites in this response.

Topics: Animals; Arousal; Enkephalin, Leucine-2-Alanine; Feeding Behavior; Indoles; Male; Morphinans; Naloxone; Naltrexone; Narcotic Antagonists; Nociceptors; Rats; Rats, Sprague-Dawley; Receptors, Opioid, mu

A series of experiments provided evidence for the existence of a functional opioid system in the fetal rat near term. Application of a tactile probe to the perioral region of the fetus consistently evoked a stereotypic facial wiping response. Administration of low dosages of morphine to the fetus had little effect on nonevoked motor activity but reduced fetal responsiveness to cutaneous stimulation. Milk infused into the mouth of the fetus reduced fetal responsiveness to the tactile probe. Milk's effect on cutaneous responsiveness was reversed by injection of the nonspecific opioid antagonist naloxone. The effect of milk on fetal responsiveness to cutaneous stimulation was reversed by the kappa opioid antagonist nor-binaltorphimine, but not by the mu antagonist beta-funaltrexamine. Milk engages the endogenous opioid system of the fetal rat and affects fetal responsiveness by interacting with the kappa receptors of the opioid system.

Topics: Aging; Animals; Arousal; Chemoreceptor Cells; Dose-Response Relationship, Drug; Female; Fetal Movement; Gestational Age; Morphine; Motor Activity; Naloxone; Naltrexone; Pregnancy; Rats; Receptors, Opioid; Receptors, Opioid, kappa; Sucking Behavior; Taste; Touch

The present study explores developmental changes in mu- and kappa-opiate receptor control of PRL secretion. The ontogeny of mu- and kappa-receptor function was determined by assessing the PRL response to the mu-agonist sufentanil (SUF) and the kappa-agonist U50488 in 5-, 10-, 15-, 20-, and 60-day-old rats. Both mu- and kappa-agonists stimulated PRL secretion at all ages. The selectivity of the mu- and kappa-agonists was confirmed by selective blockade with their respective antagonists (beta-funaltrexamine and nor-binaltorphimine). Serotonin mediation of opiate-induced changes in PRL secretion was explored across ontogeny by testing cyproheptadine (CYPRO) blockade of agonist responses in 5-, 10-, 20-, and 60-day-old rats. CYPRO attenuated the PRL response to the mu-agonist SUF in 20- and 60-day-old rats, but not in the 5- or 10-day-old pups. CYPRO did not block the kappa-agonist U50488 at any age. Similarly, pretreatment with parachlorophenylalaine lowered the PRL response to SUF in 60-day-old rats, but not in 10-day-old rats. These results support previous reports of a serotonin-mediated mu control of PRL secretion that develops by day 20 and a kappa control of PRL secretion that is independent of serotonin at all ages. These findings also suggest that a previously reported serotonin-independent mu-receptor-mediated control of PRL secretion can be stimulated early in ontogeny.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Aging; Animals; Cyproheptadine; Female; Kinetics; Male; Naltrexone; Prolactin; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin; Sufentanil

This study was undertaken to assess the sensitivity of nitrous oxide (N2O) analgesia to antagonism by intrathecally (IT) and intracerebroventricularly (ICV) administered antagonists selective for kappa- and mu-opioid receptors. Male ICR mice were pretreated IT or ICV with the kappa antagonist nor-binaltorphimine (nor-BNI), 1 or 50 nmol, respectively, or distilled water (control), then exposed to N2O (50% or 75% in oxygen). Compared with IT control mice, IT nor-BNI-pretreated mice responded with significantly less analgesia. Compared with ICV control mice, ICV nor-BNI-pretreated mice also showed markedly reduced analgesic response. Other mice were pretreated IT or ICV with either the selective and irreversible mu antagonist beta-funaltrexamine (beta-FNA, 5.0 micrograms) or distilled water (control). When exposed to N2O 24 h later, beta-FNA-pretreated and control mice exhibited comparable analgesic responses. These preliminary results suggest that N2O analagesia in mice may involve spinal and supraspinal kappa-opioid receptors but not mu-opioid receptors.

Topics: Analgesia; Animals; Binding, Competitive; Injections, Intraventricular; Injections, Spinal; Male; Mice; Naltrexone; Nitrous Oxide; Receptors, Opioid; Receptors, Opioid, kappa; Receptors, Opioid, mu