Search

The interaction between the antinociceptive activity of ketoprofen and adrenergic agents was evaluated in the writhing test of mice. Dose-response curves were obtained for systemic and intrathecal antinociceptive effects of ketoprofen, phenylephrine, clonidine, desipramine, and prazosin; and ED50were calculated. The interactions were evaluated by isobolographic analysis of the systemic or intrathecal co-administration of fixed-ratio combinations of ketoprofen with each adrenergic agent. The intraperitoneal combinations of ketoprofen with phenylephrine, clonidine, and prazosin showed supra-additivity, indicating that activation of α1and α2adrenoceptors play a role in nociceptive transmission at supraspinal levels. The same combinations given intrathecal were only additive. Desipramine intraperitoneal was also supra-additive; however, when ketoprofen was administered intrathecally with desipramine, only an additive interaction was obtained. The supra-additive interactions suggest that complementary mechanisms of antinociception have been activated, related with interference with the multiplicity of receptors and systems involved in the transmission of the nociceptive information. Racemic ketoprofen has an antinociceptive activity which is probably not only due to COX inhibition but also involves noradrenergic systems at spinal and supraspinal levels.

This study represents the first investigation demonstrating the contractile response to exogenous acetylcholine (ACh) in the isolated human vas deferens. Pharmacological characterization of cholinergic receptors was achieved using selective antagonists to define receptor subtypes. In the HVD the effect of exogenous ACh is revealed as a dose-dependent sudden increase in the basal tension of the vasa. The ACh receptors of the HVD were competitively antagonized by atropine (ATR) with a high pA2 value (8.78). The main finding of this study is the presence of cholinergic receptors of the pharmacologically defined M2-ACh subtype in the isolated HVD, according to the pA2 values obtained with pirenzepine (PRZ) 7.39, AF-DX 116 (AF) 5.92 and 4-DAMP 5.65, M1-ACh, M2-ACh and M3-ACh selective antagonists, respectively. Prazosin (PZ), a selective α1-adrenergic antagonist, displayed a similar competitive antagonism for the contractile response evoked both by ACh (pA2 = 8.69) and NE (pA2 = 8.58) in the HVD. The antagonism exerted by PZ on the ACh-induced contractile response of the HVD, suggests that ACh probably acts at a presynaptic level stimulating the release of NE from an adrenergic neuron. According to these findings, the receptor involved in this action, located in the proximity of the nerve terminals, seems to be of the M2-ACh subtype.

The antinociceptive activity of antidepressant drugs is poorly understood. In this study, using the acetic acid writhing test in mice, the antinociception produced by clomipramine (CLO), maprotiline (MAP), imipramine (IMI), and zimelidine (ZIM) was tested and correlated with opioid drugs. All the compounds displayed a significant dose-dependent antinociception, which was not antagonized by naloxone (NX) or naltrexone (NTX). The administration of morphine (M) plus CLO, MAP, IMI or ZIM resulted in a significant additive effect that was antagonized by 1 or 10 mg/kg NX or NTX, except in the case of IMI. This finding suggests that the additive effect seems to be partially due to activation of opioid receptors, except for the case of imipramine. However, aminophylline, a non-selective blocker of A1/A2 adenosine receptors, significantly antagonized the antinociceptive activity of CLO, IMI, MAP and ZIM, demonstrating an interaction at the level of adenosine receptors. This work suggests that the antinociceptive activity of antidepressants could be dependent on critical levels of free 5-HT and NE at receptor(s) site(s) in CNS and on their interaction with opioid and adenosine receptors.

The antinociceptive activity of the antidepressant agents imipramine, maprotiline and amitriptyline and their interactions with morphine and aminophylline were evaluated using the acetic acid writhing test of mouse. All the antidepressants induced a dose-dependent antinociceptive activity with a rank of potency was amitriptyline > maprotiline > imipramine. Antinociception was blocked by the pretreatment with 10 mg/kg of aminophylline, suggesting an interaction of these agents with adenosine receptors, which may cause the release of adenosine at neuronal level and depression of neuronal activity by inhibition of neurotransmitter release. Isobolographic analysis demostrated that the simultaneous administration of imipramine or maprotiline plus morphine (10:1 and 4.5:1 respectively) produced a supra-additive interaction, but the combination of amitriptyline and morphine (1:1) resulted in simple additivity. These effects were not antagonized by 1 or 10 mg/kg of aminophylline. The interaction between morphine and antidepressants seems to be due to an upregulated neuronal activity (i.e. indirect antagonism of the effect of the tricyclic agents) which could be dependent on the pharmacological profile of antidepressants with respect to their inhibition of bioamines uptake. Since antinociception was induced by acute administration of antidepressants, this action seems to be independent of antidepressive properties, which are obtained only after chronical administration. © 1997 John Wiley & Sons, Ltd.

Controlled hemorrhagic hypotension in anesthetized dogs causes progressive increases in dopamine beta-hydroxylase (DBH) and catecholamine (CA) plasma levels and in heart rate. The concentration (units per milliliter) and the calculated total plasma content of DBH activity [(units circulating + reservoir + samples] increased 2.6 and 2.3 times, respectively. A significant positive correlation (P less than .001) was found between the plasma levels of DBH and CA; however, the CA plasma levels increased earlier and were of greater magnitude (10-fold) than those of DBH. These results suggest that CAs are more sensitive indicators of acute changes in adrenergic activity than DBH. Surgical bilateral adrenalectomy completely abolished the increases in circulating CA and DBH levels and in heart rate induced by the hemorrhage, independently of the percentage of blood removed. These results indicate that the adrenal glands contribute almost exclusively to the rise in plasma DBH and CA caused by the bleeding stress and that high circulating CA concentrations seem to account for the tachycardia that accompanies the hemorrhagic hypotension. The infusion of the reservoir blood with a lower DBH and CA content than that present in the animal at that time produced a rapid fall in circulating CA levels (59.2 +/- 8.9 to 10.8 +/- 3.3 ng/ml) and no change in the DBH concentration (5.43 +/- 0.42 and 5.40 +/- 0.53 U/ml). A 38% increase in the calculated total plasma content of DBH occurred with the transfusion. Due to the large size of the DBH molecules, trapping in tissues during the hemorrhagic hypotension period might have occurred. The improvement in the hemodynamic conditions caused by the transfusion would facilitate the washout of the enzyme from the tissues into the circulation.

The antinociceptive activity of several nonsteroidal anti-inflammatory drugs (NSAIDs) that were administered either intraperitoneally or intrathecally was assessed in mice by two algesiometric tests. The first was the writhing test, which assessed the abdominal constrictions that were induced by intraperitoneal acetic acid (a chemical test), and the second was the tail flick test, which measured pain responses to heat stimuli. The corresponding effective doses and their relative potencies were compared because these tests use different nociceptive stimuli with different transmission pathways. The intraperitoneal and intrathecal dose-response curves for the antinociception induced by every NSAID that was tested were parallel in the writhing test. In the tail flick test, however, only the intraperitoneal and intrathecal dose-response curves for ketoprofen, piroxicam, naproxen, nimesulide, paracetamol and diclofenac were parallel. The results obtained in this study confirm that NSAIDs possess different abilities to induce inhibition of cyclooxygenase, and they can be indirectly assessed by their different antinociceptive activities, depending on the algesiometric assays that are used. The antinociception of most NSAIDs might involve central mechanisms. The findings demonstrate the increasing importance of the spinal cord in processing and modulating nociceptive input, because intrathecal administration of NSAIDs is always more effective (in terms of potency) than systemic administration; thus, the antinociceptive efficacy of NSAIDs strongly depends on the algesiometric assay that is used and on the type of the nociceptive stimulus to which the test subject is exposed.