A. Ortega-Alvaro

Pindolol, a beta-adrenoceptor blocker/5-hydroxytryptamine1A/1B antagonist, enhances the analgesic effect of tramadol

&NA; The ability of pindolol, a beta‐adrenoceptor blocker/5‐hydroxytryptamine1A/1B antagonist, to enhance the clinical antidepressant response to selective serotonin re‐uptake inhibitors is generally attributed to a blocking of the feedback that inhibits the serotoninergic neuronal activity mediated by somatodendritic 5‐hydroxytryptamine (5‐HT)1A autoreceptors. The current study examined the ability of pindolol to enhance the analgesic effect of tramadol, an atypical centrally‐acting analgesic agent with relatively weak opioid receptor affinity and which, like some antidepressants, is able to inhibit the re‐uptake of 5‐HT in the raphe nuclei. Racemic pindolol (2 mg/kg, s.c.), rendered analgesic a non‐effective acute dose of tramadol (10–40 mg/kg, i.p.) in two nociceptive tests: a hot plate test in mice and a plantar test in rats. Moreover, (±)8‐OH‐DPAT (0.125–1 mg/kg, s.c.), a selective 5‐HT1A agonist, reduces the analgesic effect of tramadol in the same tests. These results suggest an implication of the somatodendritic 5‐HT1A receptors in the analgesic effect of tramadol and open a new adjuvant analgesic strategy for the use of this compound.

Influence of chronic treatment with olanzapine, clozapine and scopolamine on performance of a learned 8-arm radial maze task in rats

Cognitive deficit is a significant symptom in schizophrenic patients. Use of atypical antipsychotics has been demonstrated to improve some cognitive functions in schizophrenics, as well as in patients with dementia. However, side effects like sedation and muscarinic antagonism induced by these drugs have detracted from this improvement. We are interested in determining the behavioural effect of acute and chronic treatments with olanzapine and clozapine, two atypical antipsychotics, in a paradigm of working memory, and the influence on behavioural response of possible motor effects during test performance. Unspecific muscarinic antagonist scopolamine has been used for comparison. Male Wistar rats were trained on the 8-arm radial maze up to an accuracy level in choice of 80%. Distance travelled in the maze was also measured during test performance. Acute olanzapine, clozapine and scopolamine caused significant impairment of correct performance. Rats treated with olanzapine and clozapine presented a decrease in motor activity level at the same time. After the test at acute dosage, rats were chronically treated for 14 days with olanzapine, clozapine or scopolamine and 24 h after the last dose were again tested in the 8-arm radial maze. Under this procedure, chronic treatment with olanzapine, clozapine and scopolamine did not impair correct task performance and did not modify distance travelled. We concluded that the sedative effect masked a possible effect on working memory after acute administration of olanzapine and clozapine, whereas chronic treatment with olanzapine, clozapine and scopolamine did not adversely affect working memory performance. In the case of scopolamine, it suggests that chronic muscarinic antagonism does not induce memory impairment and for atypical antipsychotics, it suggests that chronic treatment induced a tolerance to acute motor effects of these drugs.

Comparison of the antinociceptive effects of ibuprofen arginate and ibuprofen in rat models of inflammatory and neuropathic pain.

AIMS Ibuprofen arginate is a highly soluble salt formed by combining racemic ibuprofen with the amino acid l-arginine. This formulation is absorbed faster, and it is safe and effective in treating many forms of mild to moderate pain. We compared the analgesic effect of ibuprofen arginate and conventional ibuprofen in rat models of pain. MAIN METHODS Mechanical and cold allodynia were assessed in the chronic constriction injury (CCI) model of neuropathic pain, and mechanical allodynia was also examined in capsaicin-injected rats (a model of central sensitization). Inflammatory hypersensitivity was assessed with the formalin test. Ibuprofen-l-arginine, ibuprofen, l-arginine or saline was administered orally on a daily basis after CCI or capsaicin injection, and the von Frey and cold plate tests were performed on days 1, 3 and 7 after CCI or capsaicin administration. In the formalin-induced inflammatory pain test, the drugs were administered 30 min before formalin injection. KEY FINDINGS Ibuprofen only exerts an antinociceptive effect in the formalin model whereas ibuprofen-l-arginine exerts antinociceptive effects on both mechanical and cold allodynia induced by CCI, mechanical allodynia induced by capsaicin injection, and in phase 2 of the formalin test, exhibiting superior antinociceptive activity to ibuprofen in all these tests. l-Arginine only exerted antinociceptive effects on cold allodynia in CCI. SIGNIFICANCE These results demonstrate that ibuprofen arginate has stronger antinociceptive effects than ibuprofen in all the models used, suggesting it might improve the therapeutic management of neuropathic and inflammatory pain.

Extracellular signal-regulated kinase activation in the chronic constriction injury model of neuropathic pain in anaesthetized rats

The role of extracellular signal‐regulated kinases (ERKs) in nociception has been explored in the last years. While in spinal cord their activation is frequently correlated with pain or acute noxious stimuli, supraspinally, this association is not so evident and remains unclear. This study aims to evaluate ERK1/2 activation in the spinal cord and brainstem nuclei upon neuropathy and/or an additional mechanical stimulus.

Interactions of acute morphine with chronic imipramine and fluvoxamine treatment on the antinociceptive effect in arthritic rats

This study was undertaken to investigate the effects induced by chronic systemic administration of two different antidepressants: imipramine (IMI), a dual serotonin-noradrenaline reuptake inhibitor, and fluvoxamine (FVX), a selective serotonin reuptake inhibitor, on the antinociceptive effect of morphine (MOR) in a paw pressure test in adjuvant-induced arthritic rats. For 30 days rats were administered with IMI, FVX or saline (SAL). On days 15 and 30, animals were tested in the paw pressure test 20 min after MOR or SAL administration. MOR induced a significant antinociceptive effect in IMI, FVX and SAL treated rats. But, at 30 days, this increase in pain threshold was significatively higher in IMI than SAL rats. This increase was not seen in FVX rats. These results suggest that a combination of opioid and mixed monoaminergic activities is effective in enhancing the antinociceptive effect of MOR in arthritic rats while only opioid and serotonergic activities have no enhancer effect.