Physiology and Pharmacology
Volume:2 Issue: 1, 1998

In this study, we investigated the effect of nicotinic receptor agonists and antagonists on the analgesic response to morphine in the formalin test. In experiments conducted in mice, nicotine produced an early dose-dependent analgesic effect. At a dose of 0.5 mg/kg, mecamylamine, a nicotinic receptor inhibitor, suppressed the analgesic effect induced by 0.1 mg/kg nicotine in both stages of the formalin test, while hexamethonium had no such effect. Atropine, a muscarinic receptor antagonist, reduced the nicotine response at doses of 5 and 10 mg/kg. Mecamylamine, hexamethonium and atropine had no effect on morphine-induced analgesia. Administered separately, the antagonists had no effect on the analgesic response either. High doses of mecamylamine lead to an increase of the pain response. We conclude that cholinergic and opioid receptors play a possible role in the analgesic effect induced by nicotine.

The paragigantocellularis (PGi) nucleus constitutes a large portion of the ventral pontomedullary reticular formation. Neurons within the PGi have been implicated in a variety of functions including cardiovascular regulation, respiratory control, pain and analgesia. Investigators have demonstrated that electrical stimulation and microinjection of L-glutamate into the PGi produce antinociception in phasic pain. In this study, we measured the analgesic effects of electrical stimulation and glutamate microinjection into the PGi using the formalin test and the tail-flick method in rats. A bipolar stimulation electrode and a guide cannula were stereotaxically inserted into the right PGi of individual rats under brief ketamine and xylazine anesthesia. One week after the implantation, a monophasic square wave (500 µs, 400 µA, 50 Hz) was delivered into the PGi for 20 seconds via the implanted electrode. Glutamate (0.5 µl, 44 nM/rat) was injected through the guide cannula. One minute after electrical stimulation or glutamate injection, the tail-flick and formalin (50 ml, 2.5%) tests were performed. The results showed that electrical stimulation and glutamate injection into the PGi caused marked antinociception in both the tail-flick and the early phase of the formalin test compared to the control rats. We conclude that electrical stimulation and glutamate injection into the PGi cause marked antinociception in phasic pain and moderate antinociception in tonic pain. These findings suggest that the PGi is also involved in alleviation of tonic pain.

The involvement of nitric oxide (NO) in the reinforcing properties of opiate reward was studied by examining the effect of a NO precursor (L-arginine) and a NO synthase inhibitor (L-NAME) on the rate of intravenous self-administration of morphine. This experiment was investigated in male albino Sprague Dawley rats (300 ± 50 g). At doses of 5 and 10 mg/kg (i.p.), L-arginine decreased morphine self- administration significantly, while 20 and 60 mg/kg doses were not significantly effective. In addition, L-arginine per se induced self-administration behavior. At doses of 0.75, 1.25, 2.5, and 5 mg/kg (i.p.), L-NAME had no effect on self-administration, whereas injection of 5 mg/kg 60 minutes before the test did increase self-administration significantly. We may therefore conclude that NO is involved in the VTA-mesolimbic pathway, and it can be involved in the psychological dependence to morphine.

In this double blind crossover study we assessed the bioequivalence of 200 mg enteric coated sodium valproate tablets manufactured by Roozdarou with 200 mg enteric coated sodium valproate (Orlept) manufactured by Desitin, Germany. Twelve healthy male volunteers were administered a single dose of 600 mg sodium valproate manufactured by Roozdarou, followed by a similar dose of Orlept, 2 weeks later. During the first 48 hours following each administration, 11 blood samples were obtained from each volunteer. Plasma levels of valproate were measured with a sensitive and selective HPLC method. Pharmacokinetic parameters were calculated for each administration to determine the bioequivalence of the two products, including maximum plasma concentration (Cmax), time to attain maximum plasma concentration (Tmax), and area under the plasma concentration-time curve (AUC). Comparison of these figures demonstrated no significant difference; therefore 200 mg enteric coated sodium valproate tablets manufactured by Roozdarou are bioequivalent to 200 mg enteric coated Orlept tablets.

Nomifensine, an antidepressant agent, competitively inhibits dopamine uptake in the caudate-putamen and nucleus accumbens and binds to both dopaminergic and noradrenergic reuptake sites in the striatum and thalamus. In this study the effect of nomifensine on anacoccygeus contraction induced by noradrenaline and electrical stimulation was investigated in rats and compared to the effect of phentolamine, an α-adrenoceptor antagonist. Nomifensine and phentolamine produced a concentration-dependent reduction in the twitch heights. IC50 values for noradrenaline were 2.7 ± 0.02 x 10-7 M in the absence and 2.04 ± 0.027 x 10-6 M in the presence of nomifensine (3 µM/ml), and 3.4 ± 0.03 x 10-6 M in the presence of phentolamine (0.1 µM/ml). We may conclude that nomifensine has α-adrenergic blocker activity similar to phentolamine.

In this study the effect of propylthiouracil-induced hypothyroidism on rat submandibular salivary gland function and the level of copper and zinc trace elements in serum and saliva were determined. Propylthiouracil (PTU) was administered to rats for 1, 2 and 3 weeks in three different groups to induce hypothyroidism. Pilocarpine was administered under anesthesia and pure samples of saliva were collected to measure flow rate and copper and zinc levels. All the treated groups had a significant reduction in flow rate that correlated to the duration of PTU treatment. The concentration of copper in serum and saliva showed a significant increase, whereas zinc levels did not show a significant change in saliva, and decreased in serum. The weight of the salivary glands in animals treated with PTU for 2 to 3 weeks showed a significant reduction during the medication period. Therefore, we may conclude that hypothyroidism leads to changes in salivary gland function, weight, and also the level of trace elements in serum and saliva.

There is evidence that sweeteners such as sucrose and saccharin interact with endogenous opioid systems. Further research has shown that feeding different concentrations of sucrose and saccharin alter latency in the tail-flick test. In this study, the influence of a 12-day regimen of different sweetening agents, sucrose (32%), saccharin (0.08%) and aspartame (0.16%) on morphine-induced analgesia in the formalin test was investigated. Male albino mice (20-27 g) were used for the experiments. The animals were given 12 days to adapt to the dietary conditions. An initial subcutaneous injection of saline or morphine (1.5, 3, 6 or 9 mg/kg) was given 30 minutes before the observation period. Recording of the early phase began immediately and continued for 10 minutes. Recording of the late response began 20 minutes after injection and continued for 10 minutes. Sucrose and aspartame increased the analgesia of morphine in the early phase while saccharin had no effect. On the other hand saccharin and sucrose decreased the effect of morphine in the late phase while aspartame increased the effect of morphine-induced analgesia. In conclusion, the present data provide further evidence for an important role of dietary variables in determining the effects of exogenous opioids on pain sensitivity.

In this study we investigated the bronchodilatory and anticholinergic effects of the aqueous extract (AE), brewed extract (BE) and ethanol extract (EE) of Polygonum avicular in comparison with saline (S) on isolated tracheal chains of the guinea pig. Due to the probable confounding effect of ethanol in the EE, the effects of this extract were also compared with 96 % ethanol. None of the plant extracts showed any relaxant effect compared to S; neither did the EE show any significant bronchodilatory effect in comparison with ethanol. On the other hand, there was a clear rightwards shift in the methacoline log concentration-response curves obtained in the presence of AE, BE and EE in comparison with the S curve. This shift was more pronounced in the presence of AE. In the presence of AE, the methacoline EC50 showed a significant difference with that of S. The slope of the methacoline log-response curve obtained in the presence of AE was significantly lower than the S curve (p<0.001), indicating non-competitive antagonism of this solution. The difference between the slope of the methacoline-response curve of other extracts compared to the S curve was not significant, suggesting a mechanism of competitive antagonism for these solutions. In conclusion, these data demonstrate the anticholinergic effect of P. avicular, but do not show the plant extracts to have any relaxant effect. The variation of anticholinergic behaviors among different extracts is probably due to the variety of extracted substances in the different solutions.

In the present study, the effect of contralateral and bilateral electrolytic lesions of the nucleus reticularis paragigantocellularis (PGi) on tonic pain was assessed in rats. Pain-related behavior was evaluated using the formalin test 7 days after the lesion was made. PGi lesions did not produce any marked changes in the early phase of the formalin test, but significantly increased pain sensitivity in the late phase compared to the sham-operated group. Furthermore, there was no significant difference between contralateral and bilateral lesions. Since PGi lesions resulted in significant hyperalgesia, we may conclude that this region of the rostroventral medulla plays a modulatory role in the regulation of tonic pain induced by formalin as a noxious chemical stimulus.

Numerous studies conducted in laboratory animals and humans indicate that angiotensin converting enzyme inhibitors reinforce memory and learning. In this paper we study the effect of injection of enalapril into the cerebral ventricles on spatial memory of white mice in the double- y maze, following the induction of an Alzheimer- like amnestic model with scopolamine. To estimate the duration of working memory, the adaptive response method was used following a temporal pause. Animals completing the training period were injected with 2.5 mg intraperitoneal scopolamine. Injection of this dose that was determined by the dose-response curve led to a significant decrease in the percentage of correct responses of working memory (p<0.01), without any effect on reference memory. Response delay time significantly increased in both types of memory (p<0.01). Therefore, an Alzheimer-like amnestic model was induced by this dose with a relatively isolated effect on current memory. Following induction of this amnestic model in mice, the effects of 3, 5 and 10 µg injections of enalapril on the percentage of correct responses and delay time were measured without pause and also by the adaptive response method with 5 and 30 second pauses. Enalapril led to an increase in correct responses of working memory in all doses without pause (p<0.01), while this effect was only observed at 3 and 10 µg doses of enalapril with pause (p<0.05). Enalapril led to a decrease in response delay in both types of memory (p<0.05). Considering these results and previous studies, it seems that enalapril blocks the inhibitory effect of endogenous angiotensin II on the cholinergic memory centers, and thereby leads to a reinforcement of memory, especially working memory.