The effect of naloxone on trigemino-hypoglossal reflex inhibited by periaqueductal central gray stimulation in rats.

The aim of the study was to determine whether opioid receptor antagonist naloxone abolishes the influence of periaqueductal central gray (PAG) on nociceptive evoked tongue jerks (ETJ) - a trigemino-hypoglossal reflex induced by tooth pulp stimulation. In rats under chloralose anesthesia three subsequent series of perfusions of lateral ventricles - cerebellomedullary cistern with Mc Ilwain-Rodnight's solution, Met-enkaphalin (Enk-Met) and naloxone were carried out. The amplitudes of tongue jerks induced by tooth pulp stimulation were recorded during subsequent 10 min perfusions. Mean amplitude of tongue movements induced by tooth pulp stimulation was regarded as the indicator of the magnitude of trigemino-hypoglossal reflex. We observed that perfusion of the cerebral ventricles with Enk-Met (100 nmol/mL) inhibited the trigemino-hypoglossal reflex by 46%, whereas naloxone (100 nmol/mL), added to the solution perfusing the cerebral ventricles system, increased the reflex by 42%. The amplitude of ETJ was significantly reduced during PAG stimulation with a train of electrical impulses. After obtaining a significant 93% - inhibition of ETJ, naloxone (100 nmol/mL) was added to the perfusion fluid. This led to a significant increase of the reflex by 68%. The above results suggest that the inhibition of ETJ due to PAG stimulation is partially reversed by naloxone and mediated via interactions with endogenous opioid systems involved in modulation of nociception.     

Effect of galanin on substance P- and vasoactive intestinal polypeptide-induced nociceptive trigemino-hypoglossal reflex in rats.

Substance P (SP), vasoactive intestinal polypeptide (VIP) and galanin (GAL), present in primary sensory neurons, are involved in transmission of nociceptive signaling from the peripheral to central nervous system. In this study we investigated the effect of GAL on SP-induced or VIP-induced evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation during perfusion of the cerebral ventricles with SP or VIP solutions. The experiments were carried out on rats under chloralose anesthesia. It was shown that both, SP and VIP, perfused through the cerebral ventricles enhanced the ETJ amplitude as compared with control, but the effect produced by SP was stronger. The intracerebroventricular perfusion of GAL 5 minutes before SP caused a dose-dependent inhibition of SP-induced ETJ, whereas GAL perfused through the cerebral ventricles 5 minutes before VIP did not reduce the excitatory effect of VIP on ETJ. These results indicate that the antinociceptive effect of GAL perfused through the cerebral ventricles, tested on the trigemino-hypoglossal reflex in rats, is specifically mediated by the SP-ergic system.     

Interactions of galanin with endomorphin-2, vasopressin and oxytocin in nociceptive modulation of the trigemino-hypoglossal reflex in rats

Galanin (GAL) is suggested to be a neuropeptide involved in pain transmission. In this study we tried to determine, whether the increase of GAL concentration in brain cells affects impulse transmission between the motor centers localized in the vicinity of the third and fourth cerebral ventricles. The experiments were carried out on rats under chloralose anesthesia. The study objectives were realized using the method allowing to record the amplitude of evoked tongue jerks (ETJ) in response to noxious tooth pulp stimulation during the perfusion of the cerebral ventricles with solutions containing tested compounds. Perfusion of the cerebral ventricles with GAL concentration-dependently inhibited the ETJ amplitude. The antinociceptive effect of GAL was blocked by a galanin receptor antagonist, galantide (GLT) and by opioid antagonists: non-selective naloxone (Nal) and micro-selective beta-funaltrexamine (beta-FNA). In contrast, a delta-opioid receptor antagonist, naltrindole (NTI) or the kappa-opioid receptor antagonist, nor-binaltrophimine (nor-BNI) did not inhibit the effect of GAL. The antinociceptive effect of GAL was more pronounced when GAL was perfused in combination with other neuropeptides/neurohormones, such as endomorphin-2 (EM-2), vasopressin (AVP) and oxytocin (OT). The present results demonstrate that in the orofacial area analgesic activity is modulated by GAL, OT and AVP and that EM-2-induced antinociception involves GAL.     

Stressors produce a concurrent decrease and increase in reflex amplitude in rats treated with naloxone

The effect of inescapable foot-shock on the tail-flick response and on the startle response to brief shocks and brief tones was studied in rats. In the first experiment, 25 minutes of inescapable foot shock (stressor) produced a significant increase in tail-flick latency which was antagonized by the opioid antagonist naloxone (2.0 mg/kg). In the second experiment, the startle response to an electric shock to the tail was significantly diminished by the stressor, and this effect was not significantly reduced by naloxone. However, the size of the startle response to a brief tone was significantly increased in rats treated with naloxone. Thus, rats injected with naloxone had a decreased startle to shock but an increased startle to tone following inescapable foot shock. Finally, tones which preceded shocks by one second produced a facilitation of the startle response to the shocks in tests that followed exposure to the stressor. This facilitation was not affected significantly by naloxone. These results indicate that the changes in the startle response following the stressor were not mediated exclusively by endogenous opioids.     

Parasympathetic reflex vasodilation in the cerebral hemodynamics of rats

We investigated the role of parasympathetic reflex vasodilation in the regulation of the cerebral hemodynamics, and whether GABA_A receptors modulate the response. We examined the effects of activation of the parasympathetic fibers through trigeminal afferent inputs on blood flow in the internal carotid artery (ICABF) and the cerebral blood vessels (rCBF) in parietal cortex in urethane-anesthetized rats. Electrical stimulation of the central cut end of the lingual nerve (LN) elicited intensity- and frequency-dependent increases in ICABF that were independent of changes in external carotid artery blood flow. Increases in ICABF were elicited by LN stimulation regardless of the presence or absence of sympathetic innervation. The ICABF increases evoked by LN stimulation were almost abolished by the intravenous administration of hexamethonium (10 mg kg^?1) and were reduced significantly by atropine administration (0.1 mg kg^?1). Although the LN stimulation alone had no significant effect on rCBF, LN stimulation in combination with a blocker of the GABA_A receptor pentylenetetrazole increased the rCBF markedly. This increase in rCBF was reduced significantly by the administration of hexamethonium and atropine. These observations indicate that the increases in both ICABF and rCBF are evoked by parasympathetic activation via the trigeminal-mediated reflex. The rCBF increase evoked by LN stimulation is thought to be limited by the GABA_A receptors in the central nervous system. These results suggest that the parasympathetic reflex vasodilation and its modulation mediated by GABA receptors within synaptic transmission in the brainstem are involved in the regulation of the cerebral hemodynamics during trigeminal afferent inputs.     

Effect of naloxone on physostigmine-induced pressor response in adrenalectomized rats

Physostigmine-induced pressor response was studied in adrenalectomized rats. The increase in mean arterial blood pressure elicited by intravenous administration of physostigmine was not altered by adrenalectomy or sham-operation. The pressor response to intracerebroventricular administration of physostigmine was found to be partially inhibited in both acutely adrenalectomized and sham-operated rats, but not in those adrenalectomized 24 h earlier. This inhibition was completely prevented by naloxone pretreatment. The results suggest that endogenous opioid peptide release induced by surgical stress may be responsible for inhibition of the pressor effect of centrally administered physostigmine in rats.     

Effect of naloxone on hypoalgesia in rats exposed to prolonged immobilization stress

Significant hypoalgesia (tail-flick reflex at 60 degrees C) was observed in rats during the whole period of 24-hour immobilization in cramped cages, as compared to food-and-water deprived and control animals. This hypoalgesia was not antagonized by naloxone (1 mg/kg), however, the animals periodically receiving the drug during immobilization revealed aggressiveness and significant hypoalgesia after immobilization was discontinued (30-120 min observation).     

Effect of the opiate antagonist naloxone on body temperature in rats.

The specific opiate antagonist naloxone was used to assess the hypothesis that an endogenous opioid plays a significant role in temperature regulation in the rat. A very slight hypothermic effect was observed at a naloxone dose sufficient to block the opiate receptors. Even under conditions of cold stress, the magnitude of the effect was so small as to lend little support to the hypothesis.     

Continuous measurement of cerebral blood volume in rats with the photoelectric technique: effect of morphine and naloxone

The validity of a photoelectric method for continuous cerebral blood volume (CBV) measurement was tested and modified for the rat's brain. A new way of introducing a miniature light source between the two hemispheres and fixing a light sensitive silicone blue cell to the outer surface of the parietal bone was developed. Light extinction factor of the rat's blood was determined experimentally (Eb rat = 1.38 +/- 0.15) in order to calculate absolute CBV value in this species, resulting in a 4.77 +/- 0.13 vol % absolute CBV value. Data obtained in anesthetized, artificially ventilated rats by simultaneous recording of CBV and local cerebral blood flow (H2-gas clearance technique) show that local hypothalamic blood flow decreased significantly after morphine (1.0 mg/kg s.c.), while total CBV remained unchanged. Opiate receptor blockade with naloxone (1.0 mg/kg s.c.) on the contrary, as well as naloxone and morphine administration, caused no change in local hypothalamic blood flow, but resulted in a significant increase of total cerebral blood volume.     

Effect of exercise on cerebral perfusion in humans at high altitude.

The effects of submaximal and maximal exercise on cerebral perfusion were assessed using a portable, recumbent cycle ergometer in nine unacclimatized subjects ascending to 5,260 m. At 150 m, mean (SD) cerebral oxygenation (rSO2%) increased during submaximal exercise from 68.4 (SD 2.1) to 70.9 (SD 3.8) (P < 0.0001) and at maximal oxygen uptake (.VO2(max)) to 69.8 (SD 3.1) (P < 0.02). In contrast, at each of the high altitudes studied, rSO2 was reduced during submaximal exercise from 66.2 (SD 2.5) to 62.6 (SD 2.1) at 3,610 m (P < 0.0001), 63.0 (SD 2.1) to 58.9 (SD 2.1) at 4,750 m (P < 0.0001), and 62.4 (SD 3.6) to 61.2 (SD 3.9) at 5,260 m (P < 0.01), and at .VO2(max) to 61.2 (SD 3.3) at 3,610 m (P < 0.0001), to 59.4 (SD 2.6) at 4,750 m (P < 0.0001), and to 58.0 (SD 3.0) at 5,260 m (P < 0.0001). Cerebrovascular resistance tended to fall during submaximal exercise (P = not significant) and rise at .VO2(max), following the changes in arterial oxygen saturation and end-tidal CO(2). Cerebral oxygen delivery was maintained during submaximal exercise at 150 m with a nonsignificant fall at .VO2(max), but at high altitude peaked at 30% of .VO2(max) and then fell progressively at higher levels of exercise. The fall in rSO2 and oxygen delivery during exercise may limit exercise at altitude and is likely to contribute to the problems of acute mountain sickness and high-altitude cerebral edema.     

Effect of different doses of naloxone on the course of hemorrhagic shock in rats

Experiments on 52 Wistar rats were made to induce hemorrhagic shock by exemption of 40% blood from the jugular vein, which was followed by intravenous injection of either physiological solution or naloxone in doses of 0.4 and 1 mg/kg. Naloxone in a dose of 1 mg/kg was found to improve the animals' status as compared with the control (injection of physiological solution). On the contrary, injection of naloxone in a dose of 0.4 mg/kg led to the deterioration of the animals' status. Based on these data it is suggested that different opiate receptors play an inconclusive role in the development and progress of hemorrhagic shock induced by acute hemorrhage.     

Inhibition of an opioid-evoked vagal reflex in rats by naloxone,SMS 201-995 and ICI 154,129

Intravenous injection of opioid agonists in rats evokes a vagal reflex resulting in a fall in heart rate and blood pressure. Three opioid antagonists, naloxone, SMS 201-995, and ICI 154,129 were used to assess the nature of the opioid receptors that mediate the vagal reflex. The agonists used were morphine, Tyr-Pro-NMePhe-d-Pro-NH₂ (PLO17), and d-Ala²-Leu⁵-enkephalin (DADL). At challenge doses of morphine, PLO17, and DADL at five times the ED50 for bradycardia, the naloxone ED50 for DADL was nine times greater than that for morphine and PLO17. The pA₂ value of naloxone against DADL was significantly less than that for morphine and PLO17. The antagonist properties of SMS 201-995 were similar to those of naloxone. ICI 154,129, a putative delta receptor antagonist, was not, however, selective in its antagonism of opioid bradycardia. Both SMS 201-995 and ICI 154,129, when injected alone, produced changes in heart rate and blood pressure. The cardiovascular actions of the peptide antagonists were not affected by naloxone hydrochloride at doses up to 4 mg/kg i.v.