2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and bremazocine

Evidence from studies which utilise either opiate receptor agonists and antagonists strongly indicate a role for endorphinergic mechanisms in the control of feeding responses. Two means by which these compounds may exert an effect on feeding can be singled-out. Firstly, emerging evidence suggests that the process of achieving satiety (terminating a meal, or choice of a commodity) may be accelerated following treatments with opiate receptor antagonists. Secondly, the preference for highly palatable solutions (sweet solutions have received most attention) in two-bottle tests is blocked after injection of opiate receptor antagonists. This finding has been interpreted in terms of the abolition of the reward or incentive quality associated with the particularly attractive flavour. These two mechanisms of action may represent two aspects of a single, fundamental process. Following an introduction to rat urination model of in vivo kappa agonist activity, the consistent effect of several kappa agonists (including the highly selective U-50,488H) to stimulate food consumption is described. Recognising that members of the dynorphin group of endogenous opioid peptides are kappa receptor ligands, some with a high degree of selectivity, and the evidence the dynorphins and neo-endorphins produce hyperphagia in rats is particularly interesting. Such lines of evidence lead to the hypothesis that peptides of the dynorphin group may act endogenously to promote the expression of normal feeding behaviour.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Animals; Benzodiazepines; Benzomorphans; Butorphanol; Choice Behavior; Cyclazocine; Diuresis; Drinking; Dynorphins; Eating; Endorphins; Ethylketocyclazocine; Humans; Morphine; Narcotic Antagonists; Phenazocine; Pyrrolidines; Receptors, Opioid; Receptors, Opioid, kappa; Satiety Response

The changes in the latency for tail withdrawal in response to noxious heating of the skin induced by microinjection of opioid or serotonergic agonists into the anterior pretectal nucleus (APtN) was studied in rats. The mu-opioid agonist DAMGO (78 and 156 picomol), but not the delta-opioid agonist DADLE (70 and 140 pmol), the kappa-opioid agonist bremazocine (0.24 and 0.48 nanomol) or the sigma-opioid agonist N-allylnormetazocine (0.54 nanomol), produced a dose-dependent antinociceptive effect. The 5-HT1 agonist 5-carboxamidotryptamine (19 and 38 nanomol) and the 5-HT1B agonist, CGS 12066B (1.12 and 2.24 nanomol), but not the non-selective 5-HT agonist m-CPP (41 to 164 nanomol), 5-HT2 agonist alpha-methylserotonin (36 and 72 nanomol) and 5-HT3 agonist 2-methylserotonin (36 and 72 nanomol), produced a dose-dependent antinociceptive effect. These results indicate that the antinociceptive effects of opioid or serotonergic agonists microinjected into the APtN depend on drug interaction with local mu or 5-HT1B receptors, respectively.

Topics: Analgesics; Animals; Benzomorphans; Brain; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, Leucine-2-Alanine; Enkephalins; Male; Microinjections; Pain; Phenazocine; Piperazines; Quinoxalines; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Serotonin; Serotonin Receptor Agonists

The kappa-agonists bremazocine and dynorphin(1-13), the sigma-agonist SKF 10.047 as well as the delta-agonists [D-Ala2,D-Leu5]-enkephalin (DADL) and Met-enkephalin, but not the mu-agonist morphine, applied subarachnoidally to the caudal portion of the transected spinal cord (at the T3-T4 level) induced postural asymmetry of the hind limbs in rats. Asymmetry was registered visually. The leg was regarded as flexed if its projection on the longitudinal axis of the animal was smaller than that of its counterpart. The side of the flexed leg depended upon the type of drug: bremazocine, dynorphin(1-13) and Met-enkephalin predominantly induced flexion of the right leg, SKF 10.047 induced flexion of the left leg (at some doses there is no side preference), while in the case of DADL the side of the flexed leg depended upon the dose of the drug. Comparison of electromyographic activity of the symmetric biceps and quadriceps femoris revealed that bremazocine considerably facilitates the flexion reflex of the right hind limb without affecting the left limb reflex. As a rule, a flexed leg determined visually exhibited higher EMG activity of the biceps femoris as compared with a symmetric one. The opiate antagonist naloxone significantly reduced the percentage of animals with postural asymmetry. The magnitude of asymmetry and the side of flexion were not constant in some animals, but changed with time. However, the mean magnitude of asymmetry, the percentage of animals with asymmetry and the left/right flexion ratio in each group of animals remained constant. The side of flexion also depended upon the level of spinal cord transection: bremazocine and Met-enkephalin injected subarachnoidally following transection at the T1-T4 and T5-T6 levels predominantly induced flexion of the right and the left leg, respectively. Asymmetry did not develop in physiologically intact animals given bremazocine, even if the spinal cord was cut later, i.e. transection of the spinal cord was necessary for the development of asymmetry. These data indicate that the neurons which maintain muscular tone of the hind limbs and which are located symmetrically to the sagittal plane, have different sensitivities to kappa-, sigma-, and delta-agonists. In most animals, neurons with a higher specificity to some agonist are localized on one side of the sagittal plane.

Topics: Animals; Benzomorphans; Decerebrate State; Enkephalin, Leucine; Enkephalin, Leucine-2-Alanine; Functional Laterality; Male; Muscles; Naloxone; Narcotics; Phenazocine; Posture; Rats; Rats, Inbred Strains; Receptors, Opioid; Spinal Cord; Time Factors

The effects of several opioid agonists and the opioid antagonist naloxone were examined in rats responding under a fixed-consecutive-number (FCN) schedule. Under this schedule, a reinforced response run consisted of responding eight or more times on one response lever, and then responding once on a second response lever. In one component of this schedule, an external discriminative stimulus signalled the completion of the response requirement on the first lever, whereas no stimulus change was programmed in the other. Morphine, l-methadone, U50488, ketocyclazocine, phencyclidine, and (+/-)N-allylnormetazocine decreased the percent of reinforced response runs (accuracy) under the FCN schedule without the external discriminative stimulus, but had no effect under the FCN schedule with the external discriminative stimulus. Naloxone and bremazocine, in contrast, had no effect on the accuracy of the discrimination under either FCN schedule. With the exception of bremazocine and U50488, which increased rates of responding at low doses, all drugs produced comparable decreases in rates of responding under both FCN schedules. During tests of antagonism, a 0.1 mg/kg dose of naloxone reversed completely the accuracy-decreasing effects produced by U50488 and morphine. The rate-decreasing effects of morphine and U50488 were reversed completely by a 0.01 and 1.0 mg/kg dose of naloxone, respectively. These results suggest that the addition of an external discriminative stimulus can modulate the disruptive effects of opioids, and that mu, sigma and some kappa agonists produce similar effects when evaluated under the FCN schedules.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Benzomorphans; Conditioning, Operant; Cyclazocine; Discrimination Learning; Ethylketocyclazocine; Male; Methadone; Morphine; Naloxone; Narcotics; Phenazocine; Pyrrolidines; Rats; Reinforcement Schedule

Slices of rat substantia nigra were preloaded with tritiated gamma-aminobutyrate (GABA) or dopamine (DA) and perfused with Krebs solution containing 5 microM aminooxyacetic acid or 10 microM nialamide to inhibit the catabolism of GABA and DA respectively. Repeated brief exposures to high potassium medium (+ 30 mM K+ for 1 min) evoked a consistent pattern of calcium-dependent 3H efflux against which the effects of opiates (10-400 microM) were assessed. Opiate agonists inhibited K+-induced 3H-GABA efflux in the following decreasing order of potency: bremazocine greater than D-Ala2-Met5-enkephalinamide (ENK) greater than SKF 10047 much greater than morphine, consistent with the participation of kappa, delta, sigma and to a lesser extent mu opiate receptors respectively. Naloxone (1 microM) partially antagonised the response to morphine and ENK, while ICI 154129 attenuated ENK only. Save for a GABA-releasing action of SKF 10047 at high doses, none of the compounds altered basal outflow of 3H-GABA. Naloxone, in the dose range 10-400 microM, also significantly inhibited depolarisation-induced release of 3H-GABA. In parallel experiments none of the compounds tested were found to influence 3H-DA release in concentrations up to 40 microM, but thereafter suppressed K+-induced 3H-DA outflow indiscriminately. The results are discussed with reference to the possible mechanism(s) via which injected and endogenous opiates may affect motor performance by attenuating GABA transmission in the nigra.

Topics: Aminooxyacetic Acid; Animals; Benzomorphans; Dopamine; Enkephalin, Methionine; Female; gamma-Aminobutyric Acid; Male; Naloxone; Nialamide; Phenazocine; Rats; Rats, Inbred Strains; Receptors, Opioid; Secretory Rate; Substantia Nigra

The hypothesis that the nociceptive state and opiate-induced antinociception are generally regulated by Ca2+ brain levels has been tested. In this context, the effects of intracerebroventricular injections of CaCl2 (0.1-0.5 mumol), D600 (5.0-10.0 micrograms) and EGTA (0.5-1.0 mumol) on ethylketocyclazocine (EKC), ketocyclazocine (KC), Mr-2033, pentazocine (PTC), bremazocine (BMC) and SKF 10,047-induced antinociception were investigated in the mouse tail immersion test. Simultaneous treatment with either D600 or EGTA resulted in a significant and dose-related enhancement in the activities of the kappa-agonists: EKC, KC and Mr-2033, whilst the activities of PTC, BMC and SKF 10,047 remained unchanged. CaCl2 readily blocked the activities of all benzomorphans tested except that of SKF 10,047 against which CaCl2 was less effective. In addition a dose-related hyperalgesia was observed when CaCl2 was given alone. Although the results obtained from the kappa-agonists and CaCl2 per se support the hypothesis in question, data obtained from PTC, BMC and SKF 10,047 tends to oppose it. Additionally the present results taken together indirectly substantiate the notion that benzomorphan-induced analgesia may involve different opiate-sensitive neuronal substrates.

Topics: Analgesia; Analgesics; Analgesics, Opioid; Animals; Benzomorphans; Calcium; Calcium Channel Blockers; Cyclazocine; Egtazic Acid; Ethylketocyclazocine; Gallopamil; Male; Mice; Morphinans; Pentazocine; Phenazocine

The discriminative stimulus properties of nalorphine were studied in rhesus monkeys trained to discriminate i.m. injections of nalorphine (1 mg/kg) from saline. During training, a two-lever paradigm was employed where a single, 3-min extinction schedule was followed by fixed-ratio-20 schedules of food presentation. During the fixed-rate schedules, responses on one of the two levers produced food when nalorphine had been administered and responses on the other lever produced food when saline had been administered. During stimulus generalization tests, responses on either lever produced food under the fixed-ratio schedule. The discriminative stimulus effects of nalorphine were antagonized by naloxone which, by itself, did not generalize to nalorphine. The kappa opiate agonists, ethylketocyclazocine, U-50,488, bremazocine, tifluadom, as well as two mixed kappa-sigma agonists, dl-cyclazocine and dl-N-allylnormetazocine (SKF-10047), generalized to nalorphine with the following potency ranking order: bremazocine greater than ethylketocyclazocine greater than tifluadom greater than cyclazocine greater than U-50,488 greater than N-allylnormetazocine greater than nalorphine. The levo-isomers of cyclazocine, N-allylnormetazocine or U-50,488 generalized to nalorphine whereas the dextroisomers did not. Generalization to nalorphine did not occur with the mu opiate agonists, morphine, methadone and meperidine, or the nonopiate compounds, phencyclidine, ketamine and chlorpromazine. The results suggest that a kappa opiate receptor mechanism mediates the discriminative effects of nalorphine in the rhesus monkey, which may also be involved with the naloxone-sensitive, sedative and dysphoric effects of nalorphine in humans.

Topics: Animals; Benzodiazepines; Benzomorphans; Conditioning, Operant; Cyclazocine; Discrimination Learning; Dose-Response Relationship, Drug; Ethylketocyclazocine; Macaca mulatta; Male; Nalorphine; Naloxone; Phenazocine; Receptors, Opioid; Receptors, Opioid, kappa