Intrathecal morphine, but not buprenorphine or pentazocine, can induce spastic paraparesis after a noninjurious interval of spinal cord ischemia in the rat.

In this study, we sought to determine the effect of intrathecal (IT) pentazocine or buprenorphine on the neurological outcome after a short interval of spinal cord ischemia in rats. Although IT morphine (30 microg) induced spastic paraparesis after 6 min of aortic occlusion, neither pentazocine (150 microg) nor buprenorphine (4 microg) produced neurological dysfunction. Our results indicate that the effect of various opioids on the motor function after a noninjurious interval of spinal cord ischemia is opioid-specific.

Effect of drugs influencing central serotonergic mechanisms on pentazocine-induced catalepsy in mice.

Cataleptic effect of pentazocine in mice was affected by pretreatment with dexfenfluramine, fluoxetine, buspirone, p-chlorophenylalanine, cyproheptadine, mianserin, cisapride, ondansetron, pindolol and propranolol. The results suggest that drugs which influence the activity of central serotonergic systems do modulate pentazocine-induced catalepsy in mice.

The effect of drugs on the mortality of mice inoculated with Friend leukaemia virus or toxoplasma gondii.

Infection and tumors provoke substantial changes accompanied with the disbalance of many neuroendocrine factors which in their summarizing effects influence the life span of animals. Our previous results showed enhanced mortality after one injection of morphine in association with Friend leukaemia virus infection. The aim of this study was to examine the effects of some other opioids (pethidine and pentazocine) and an acetylcholine esterase inhibitor neostigmine on the survival of animals under two conditions: (1) Friend leukaemia virus infection which mostly depressed immune functions, and (2) Toxoplasma gondii infection which in general enhanced the immune status. In contrast to our previous observation with morphine, the mortality induced by single doses of pethidine (150 mg/kg) or pentazocine (50-75 mg/kg) was unchanged during the Friend leukaemia virus infection. A single injection of neostigmine (0.42 or 0.56 mg/kg) was significantly more lethal in DBA-2 mice infected with Friend leukaemia virus. Neostigmine in doses of 0.33 and 0.4 mg/kg caused death in 46 % and 57 %, respectively, of animals infected with Toxoplasma gondii which was significantly higher in comparison with only 8 % and 12.5 % in control groups. Pethidine (150 mg/kg) killed 70 % of Toxoplasma gondii infected animals and even 90 % of non-infected mice. Thus, the Friend leukaemia virus and Toxoplasma gondii infections increased toxicity only of some drugs which may, at least partly, be associated with altered immune status during infection and involvement of the cholinergic system.

Effects of pentazocine in experimental head injury.

In previous studies we demonstrated the adverse effects of ethyl alcohol in murine head injury. Using this model in this study, effects of prior administration of pentazocine (Talwin) on the survival of mice are reported. Swiss Webster mice were randomly divided into one of three groups. Group I (n = 20) received pentazocine and Group II (n = 20, controls) received saline. Groups I and II were then injured under ether anaesthesia by allowing a weight to fall from a height of 15 cm on the cranium. Ten animals received pentazocine and were anaesthetized but had no head trauma (Group III). In Group II, 85% survived 24 h, and in Group I, 35% survived; all mice in Group III survived 24 h (significance: chi 2, p less than 0.005; Group I versus Groups II and III). Pentazocine increases the lethality of murine head injury.

Pulmonary hypertensive response to foreign body microemboli.

Pulmonary hypertension and foreign body granulomas are recognized sequelae of chronic intravenous drug abuse. We have recently described the development of transient pulmonary hypertension and increased permeability pulmonary edema after the intravenous injection of crushed, suspended pentazocine tablets in both humans and dogs. To determine the role of vasoactive substances in the development of this transient pulmonary hypertension, we measured pulmonary hemodynamics and accumulation of arachidonic acid metabolites in dogs during the infusion of indomethacin, a cyclooxygenase inhibitor, diethylcarbamazine (DEC), a lipoxygenase inhibitor, and FPL 55712, a receptor antagonist for leukotriene C4/D4 (LTC4/D4). Following the intravenous administration of crushed, suspended pentazocine tablets (3-4 mg/kg of body weight), mean pulmonary artery pressure increased from 14 +/- 2 mmHg to 30 +/- 6 mmHg (p less than 0.05) at 60 secs with a concomitant increase in plasma concentrations of 6-keto-PGF1 alpha from 187 +/- 92 pg/ml to 732 +/- 104 pg/ml and thromboxane B2 from 206 +/- 83 pg/ml to 1362 +/- 117 pg/ml (both p less than 0.05). Indomethacin prevented the increase in both cyclooxygenase metabolites, but had no effect on the pulmonary hypertension. In contrast, DEC had no effect on the increase in cyclooxygenase products, but blocked the pulmonary hypertension. FPL 55712 did not effect either the increase in cyclooxygenase metabolites or the pulmonary hypertension. We conclude that the transient pulmonary hypertension, induced by the intravenous injection of crushed, suspended pentazocine tablets, is not mediated by cyclooxygenase products but may be mediated by lipoxygenase product(s) other than LTC4/D4.

Pulmonary response to foreign body microemboli in dogs: release of neutrophil chemoattractant activity by vascular endothelial cells.

Pulmonary hypertension and foreign body granulomas are complications of the chronic intravenous injection of crushed, suspended pentazocine (Talwin) tablets. To evaluate the early cellular mechanisms underlying the response of the lung to foreign body microemboli, we examined lung histopathology and bronchoalveolar lavage (BAL) fluid in dogs for accumulation of inflammatory cells shortly after the injection of crushed, suspended pentazocine tablets. We found that the injection of suspended pentazocine tablets is associated with the rapid accumulation of neutrophils around intravascular talc crystals but not within the alveolar airspaces. To determine the cause of the observed neutrophil accumulation, we assayed plasma and lavage fluid for neutrophil chemoattractant activity (NCA). NCA appeared in pulmonary arterial (PA) and left ventricular (LV) plasma within 60 s of injection of the suspended tablets. However, there was no evidence of NCA in BAL. To determine whether appearance of chemoattractant activity found in plasma was modified by inhibitors of arachidonic acid metabolism, we infused dogs with indomethacin, diethylcarbamazine (DEC), or FPL 55712 and assayed plasma for NCA after the injection of suspended pentazocine tablets. We found that the appearance of NCA is prevented by the infusion of either DEC or FPL 55712 but not by the infusion of indomethacin. We found that cultured pulmonary arterial or aortic endothelial cells also release NCA when incubated with either the suspended pentazocine tablets or talc. Extraction with acidified diethyl ether partitioned all the NCA into the organic phase. The release of NCA from cultured endothelial cells was likewise prevented by coincubation with DEC or FPL 55712 but not by coincubation with indomethacin.(ABSTRACT TRUNCATED AT 250 WORDS)

Behavioral and developmental effects of prenatal exposure to pentazocine and tripelennamine combinations.

Long-Evans, hooded rats were intubated with one of four dose combinations of pentazocine and tripelennamine on Days 7-20 of pregnancy: 0:0 (mg/kg pentazocine:tripelennamine), 20:10, 40:0, or 40:20. An additional group had free access to lab chow and water throughout pregnancy. At birth, reduced body weights were evident in all drug-treated offspring. Growth deficits were not noted at 5, 10, 15 or 20 days of age. Three measures of activity were collected at 18 days of age, however, none of these measures were differentially affected as a function of prenatal treatment. At 85 days of age, offspring were tested in a two-way shuttle avoidance paradigm. Although the number of avoidances was not significantly affected by prenatal treatment, offspring exposed to these drugs in combination had shorter response latencies than controls with increased training and made more intertrial crossing responses. Additional offspring were tested for seizure susceptibility at 100 days of age. None of the parameters of seizure activity were significantly affected by prenatal drug treatment. Prenatal exposure to pentazocine and tripelennamine resulted in prenatal growth deficits, increased activity during the intertrial interval and decreased response latencies in a shuttle avoidance learning task, suggesting that this polydrug combination may be associated with some long-term behavioral teratogenic risks.

Lethality of opioid and antihistaminic combinations in mice.

The lethality of morphine (37.5, 75, and 150 mg/kg) and tripelennamine (10,20,40 and 60 mg/kg), given alone and in combination, was evaluated in mice housed in groups of 16. When given alone, neither drug produced death at any dose. Combining the drugs produced supra-additive effects: some deaths occurred at all combination doses. The lethality of pentazocine (20, 40 and 80 mg/kg) and diphenhydramine (20, 40 and 80 mg/kg), given alone and in combination, also was evaluated. Neither drug alone produced death at any dose. Supra-additive effects were observed when the drugs were combined. These results are similar to earlier findings concerning the lethality of combinations of pentazocine and tripelennamine.

Differentiation of multiple analgesic opiate receptors.

In order to analyse opiate receptors mediating anti-nociception, the activity pattern of different opiates was determined by using hot-plate (45 degrees C and 56 degrees C), tail-flick and algolytic tests on rats, and the acetic acid stretching test on mice, for evaluation of analgesic activity. Potentiation of barbiturate anaesthesia, measurement of pupillary diameter, and a modification of pentetrazol convulsion, were used for evaluation of non-analgesic activity. The efficacy and affinity constant (pA2) of the proposed opiate A receptor agonist and B receptor antagonist drug N-cyclopropylmethyl-norazido-dihydroisomorphine (CAM) were determined. CAM produced several opiate agonist (morphine-like) effects, often stronger than morphine, in three of the analgesic tests and two of the non-analgesic tests. On the other hand CAM proved to be a very strong narcotic antagonist, as potent as naloxone as evidenced by identical pA2 values, in the algolytic, 45 degrees C hot-plate and pentetrazol tests, but not in the 56 degrees C hot-plate, tail-flick and acetic acid tests. The potency differences for the actions of morphine and CAM in a heat test (56 degrees C hot-plate) compared with a non-heat test (acetic acid stretching) were found to be 8.6 and 540 respectively. It is concluded that opiate analgesia might be mediated by at least two receptors classified in terms of the antagonistic or agonistic activity of CAM.

Lethality of pentazocine and tripelennamine combinations in mice housed individually and in groups.

Lethality of 80 mg/kg pentazocine alone; 40 mg/kg tripelennamine alone; 20 mg/kg tripelennamine in combination with 40, 60, and 80 mg/kg pentazocine; and 40 mg/kg tripelennamine in combination with 10, 20, and 40 mg/kg pentazocine was determined in mice housed individually and in groups. Results indicate that the lethality of pentazocine and tripelennamine combinations in mice is (1) dose-dependent, (2) potentiated relative to either drug alone, and (3) greater in group-housed than in individually-housed animals.

Potentiation of lethality in mice by combinations of pentazocine and tripelennamine.

Quantal dose-response curves were generated to determine the median lethal doses (LD50S) for pentazocine and tripelennamine, either alone or in combination. LD50S of the drug combinations in mice demonstrated significant potentiation when compared with either drug administered alone. Attempts to antagonize the lethality of such combinations have, to date, been unsuccessful.

[The study of developmental pharmacology (I). Effect of pentazocine HCl on the physiology of rats given the drug during perinatal and postnatal periods (author's transl)].

The effects of drug administration on the dams (F0) and their offspring (F1), particularly on the central nervous and reproductive functions of F1, were studied by oral administration of pentazocine HCl to rats during the perinatal and postnatal periods. No significant differences were observed between administered and control rats regarding body weight changes and food intake during perinatal and postnatal periods in F0 at all dosages, but temporary salivation was observed in the 200 and 100 mg/kg groups, and decline of spontaneous activity and respiratory rate, disappearance of righting reflex, clonic convulsion were observed in some of the 200 mg/kg group. No significant differences were observed regarding litter size, birth rate, state and timing of differentiation as postnatal development, sex maturity, reproductive function in F1, although some groups were slightly inferior in body weight at birth and during the nursing period. Furthermore, no differences were observed in respect to the nervous functions of balance, exercise and psychotic related activity in the open-field test.

[The study of developmental pharmacology (II). Histological observations of central nervous tissue in rats of dams given pentazocine HCl during perinatal and postnatal periods (author's transl)].

In previous literature, we reported that the rats whose dams had been administerd pentazocine HCl 200 mg/kg/day during the perinatal and postnatal periods, showed no differences between control rats in the physiological function and psychotic activity tests. Brain tissues of the rats were observed histologically herein to confirm the result of previous tests. Abnormal findings such as deficits, undevelopment and metamorphosis, in the shape, size and configuration of nerve cells, myelin sheaths and vessels in consecutive transverse sections stained by Nissl and Klüver-Barrera method were not evident on examination under light microscope, and in cell bodies, dendrites, axons, myelin sheaths, synaptic complexes of nerve cell, neuroglia and vessels in the cerebral cortex, under electron microscope. The lack of abnormal findings in the histological observation of brain tissues supports the result of previously conducted physiological function and psychotic activity tests in which no significant differences were found between treated and control rats. Pentazocine HCl had no effect on the brain tissues of rat offspring from dams administered the drug during perinatal and postnatal periods.