The effects of the highly selective delta opioid receptor antagonists naltrindole (NTI) for delta 1 and delta 2 naltriben (NTB) and naltrindole 5'-isothiocyanate (5'-NTII) for delta 2 and 7-benzylidenenaltrexone (BNTX) for delta 1 on the development of physical dependence on morphine were investigated in mice. Neither NTI (3 mg/kg, sc), NTB (0.5 mg/kg, sc), 5'-NTII (0.5 mg/kg, sc) nor BNTX (0.5 mg/kg, sc) suppressed the antinociception induced by morphine (10 mg/kg, sc). Pretreatment with NTI (3 mg/kg, sc), NTB (0.5, 1.0 mg/kg, sc) or 5'-NTII (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine for 5 days significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice. The incidence of jumping and body shakes in morphine-dependent mice that were pretreated with NTI. NTB or 5'-NTII were significantly lower than with morphine alone. Pretreatment with BNTX (0.5, 1.0 mg/kg, sc) during chronic treatment with morphine also significantly suppressed naloxone-induced body-weight loss in morphine-dependent mice, but this suppression was weaker than that by the antagonists. In contrast to mice that had been pretreated with NTI, NTB or 5'-NTII, the incidence of several withdrawal signs, such a jumping and body shakes, was not significantly affected in morphine-dependent mice that were pretreated with BNTX. These findings suggest that both delta 2 and delta 1 opioid receptors may play important roles in modulating the development of physical dependence on morphine.

Analgesics, Opioid↗

PubMedDate not supplied

Elevated nitric oxide synthase activity concurrent with antigen-induced airway hyperresponsiveness in rats.

To characterize the airway nitric oxide synthase (NOS) activities concurrent with airway hyperresponsiveness (AHR), a common feature of allergic asthma, the NOS activities of airway tissue homogenates from the antigen-induced AHR rats were determined by the ability of tissue homogenates to convert L-arginine to L-citrulline (Cit). A significantly higher level of total NOS activities was found in homogenates from the AHR rats (19.9 +/- 1.3 pmol Cit/min/mg protein) compared to those from sensitized control and normal control groups (9.8 +/- 1.2 and 8.8 +/- 1.2 pmol Cit/min/mg protein, respectively; P < .01). The nitrite concentration in bronchoalveolar lavage fluids, which indicates the in vivo generation of NO in airways, from the AHR rats (7.40 +/- 0.71 microM) was significantly greater than that from nonsensitized normal animals (1.45 +/- 1.12 microM, P < .01). Although the protein levels of endothelial (eNOS) and neuronal type NOS (nNOS) determined by immunoblotting were within normal levels, the amount of inducible NOS (iNOS) protein was markedly and significantly elevated in airway tissue homogenates from the AHR rats. Immunohistochemical staining of airway tissues with specific antibody against iNOS demonstrated a distinct localization of iNOS on epithelial cells and infiltrated inflammatory cells in the bronchi of the hyperresponsive rats, but only negligible staining of epithelia was observed in the nonsensitized normal group. No difference in constitutive NOS (eNOS and nNOS) localization was observed between groups. The present findings indicate that the NOS activities in airway tissues are elevated in antigen-induced AHR rats, which is mainly derived from the induction of iNOS in the airways. Downregulation of constitutive eNOS and nNOS is not found in this animal model of AHR.

Airway Obstruction↗

PubMedDate not supplied

Teratogenic and antiteratogenic effects of nicotinamide derivatives in chick embryos.

Teratogenic and antiteratogenic effects of nine nicotinamide analogs in chick embryos were investigated. Further, the teratisms of 6-aminonicotinamide (6-AN), nicotinamide analogs, and an organophosphate (diazinon) were compared. White leghorn chick embryos were used. Agents were injected into the yolk of eggs on d 3 of incubation. Morphological observations were made on d 17 of incubation. Chemical names for compounds I to IX are: I, 6-dimethylaminonicotinamide; II, 6-diethylaminonicotinamide; III, 6-methylamino-3-(N-methyl)-nicotinamide; IV, 6-dimethylamino-3-pyrimidine carboximide; V, 6-(dimethylamino)-nicotinic acid; VI, 6-chloro-3-[N-(5-diethylamino)-2-pentyl]-nicotinamide; VII, 6-mercaptonicotinamide; VIII, [N-acetyl-N'-(3-pyridyl)-carbonyl]-hydrazine; IX, nicotinamide 1-N-oxide. The LD50 values in mumol per egg were as follows: 6-AN, 0.073; compound II, 0.23; compound III, 1.11; compound I, 1.32; compound VI, about 3. Compounds IV, V, VII, VIII, and IX showed no toxicity or lethality at the highest doses tested (10 mumol/egg). Among the nine nicotinamide analogs, compounds I, II, and III, which have an amino group at the 6-position of the pyridine ring, were teratogenic. Their teratogenic signs were similar to those caused by 6-AN: they showed growth retardation, anteriorly directed short legs, and coarse, dense feathering. The teratogenic effects of compounds I, II, and III were prevented by pretreatment with nicotinamide, as were the effects of 6-AN and diazinon. Among the nine analogs, only compound VIII had an antiteratogenic effect against the diazinon-induced micromelia (in which the cardinal signs were tibiotarsal angulations and poor feathering). For teratisms produced by 6-aminonicotinamide analogs and organophosphates, nicotinamide was an effective antiteratogenic agent. However, some differences in the malformations induced by both types of agents were found. We suggest that the addition of a 3-acetylpyridine type to the nicotinamide-related teratisms (6-AN type, 3-acetylpyridine type, and organophosphate type) will provide a clearer distinction among the types.

Animals↗

PubMedDate not supplied

Teratogenic effects of cholinergic insecticides in chick embryos. III. Development of cartilage and bone.

Teratogenic effects of two organophosphate insecticides, diazinon and dicrotophos, were investigated in regard to skeletal development, particularly of the extremities and vertebrae. Cartilage and calcified bone were examined with alcian blue and alizarin red S staining techniques, respectively, in chick embryos of d 5 to 17 of incubation. The age-related development of both cartilaginous and ossified portions of the hind leg was measured in control and insecticide-treated groups. Diazinon and dicrotophos (200 micrograms/egg), injected on d 3, inhibited growth of the following skeletal elements: femur, tibia, metatarsi and digits of the leg. The inhibition was noticeable from the 9th d of incubation. The greatest reduction of the skeletal length was observed in tibia and metatarsi, and was characterized by angulations toward the dorsal side. Percent of growth inhibition of the calcified region in the legs was similar to that of the entire length of each skeletal element, but there was no difference between control and insecticide-treated groups on the time-related appearance of cartilaginous or calcified long bones, digits, and phalanges of legs. In the cervical region of embryos treated with the insecticides, unique deformities such as an "undulating" notochord and fused cervical rings were seen at an early stage (d 6). We suggest that the organophosphate-induced malformations in legs are mainly due to growth retardation of later stages of development of each skeletal element. On the other hand, the neck deformities result from a profound alteration of differentiation at early stages of development.

Abnormalities, Drug-Induced↗