Involvement of 5-HT1A/1B receptors in the antinociceptive effect of paracetamol in the rat formalin test.

The mechanism of analgesic action of paracetamol (acetominophen) remains still unknown. However, a relationship between serotonergic system and the effect of paracetamol has been previously demonstrated. The serotonin activity in the brainstem is primarily under the control of 5-HT1A somatodendritic receptors, although some data also suggest the involvement of 5-HT1B receptors. To determine whether the 5-HT1A and 5-HT1B receptors are involved in the antinociceptive effect of paracetamol, we evaluated the effect of paracetamol (0.125-1 g/kg i.p.) followed by different antagonists [WAY 100,635 (0.8 mg/kg s.c.) and SB 216,641 (0.8 mg/kg s.c.)] or agonists [8-OH-DPAT (0.125 mg/kg s.c.) and CP 93,129 (0.125 mg/kg s.c.)] of 5-HT1A and 5-HT1B receptors, respectively, in the rat model of formalin-induced pain. We demonstrated that paracetamol administration showed a dose-dependent antinociceptive effect in the formalin test. WAY 100,635 (5-HT1A antagonist) induced an increase in the antinociceptive effect of paracetamol at 250 mg/kg doses. Conversely, 8-OH-DPAT (5-HT1A agonist) decreased the antinociceptive effect of paracetamol at 500-1000 mg/kg doses. However, SB216641 (5-HT1B antagonist) modified weakly the antinociceptive effect of paracetamol at 250 mg/kg doses and CP 93,129 (5-HT1B agonist) not produce a clear effect in the antinociceptive effect of paracetamol. These results suggest that the antinociceptive effect of paracetamol can be enhanced mainly by compounds having 5-HT1A antagonist properties in the formalin test and maybe by 5-HT1B receptors antagonists.

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.

Antinociceptive effects of tricyclic antidepressants and their noradrenergic metabolites.

This study evaluates the antinociceptive effect of several tricyclic antidepressants in four nociceptive tests which employ either thermal (hot plate and tail flick tests) or chemical (formalin and acetic acid tests) stimuli. Forced swimming test was also performed as a model of depression and an activity test was also performed. Mixed antidepressants in current clinical use: amitriptyline, imipramine and clorimipramine and their respective main secondary metabolites which preferentially inhibit noradrenaline reuptake: nortriptyline, desipramine and desmethylclorimipramine, were tested (2.5-20 mg/kg, i.p.) in mice. The results show a stronger antinociceptive effect in chemical tests induced by all the drugs, compared with thermal tests. The doses needed to produce antinociception were lower than those inducing an antidepressive effect, both effects being mutually independent. The overall results show that preferentially noradrenergic tricyclics induced an antinociceptive effect comparable with that of mixed tricyclics, indicating that noradrenaline reuptake plays an important role in tricyclic-induced antinociception.

Antidepressant-like effects of tramadol and other central analgesics with activity on monoamines reuptake, in helpless rats.

Affective states are regulated mainly by serotonin and noradrenaline. However the opioid system has been also related to antidepressant-induced mood improvement, and the mu-opioid receptor has been involved in affective responses to a sustained painful stimulus. Similarly, antidepressant drugs induce an antinociceptive effect via both the monoaminergic and opioid systems, probably involving sensorial and affective dimensions of pain. The aim of this study was to test three opiate analgesics, which also inhibit monoamine reuptake, in the learned helplessness model of depression in rats. Helpless rats receiving (+/-)tramadol (10, 20 mg/Kg) or (-)methadone (2, 4 mg/Kg) showed a decreased number of failures to avoid or escape aversive stimulus (shock) in both the second and the third daily sessions, compared with controls. Rats receiving levorphanol (0.5, 1 mg/Kg) showed a decreased number of such failures in the third session. The number of crossings in the intertrial interval (ITI) was not significantly modified by (+/-)tramadol or (-)methadone. Levorphanol enhanced ITI crosses at 1 mg/Kg. These results, together with other clinical and experimental data, suggest that analgesics with monoaminergic properties improve mood and that this effect may account for their analgesic effect in regulating the affective dimension of pain. From this, it seems probable that the analgesic effect of opiates could be induced by adding together the attenuation produced of both the sensorial and the affective dimensions of pain.

Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.

OBJECTIVE: To test the hypothesis that there is an association between susceptibility to inflammation and a hyporesponsive hypothalamo-pituitary-adrenal (HPA) axis. METHODS: Animals were separated on the basis of behaviour in the learned helplessness (LH) paradigm into groups of LH(+) (i.e. animals which did not escape footshock) and LH(-) animals. Adjuvant-induced arthritis (AA) was subsequently induced in the LH(+) and LH(-) animals. RESULTS: Plasma corticosterone was significantly increased in response to the LH test in the LH(-) compared with the LH(+) rats. We observed an earlier onset and increased inflammation in the LH(-) rats in spite of the greater corticosterone response to the acute stress. We noted lower levels of plasma testosterone in the LH(-) animals suggesting a possible influence for this protective factor in AA. CONCLUSION: These data suggest that increased onset and severity of inflammation in AA is not a simple consequence of an attenuated HPA axis response to stress as proposed in the Lewis rat. Indeed we have observed the converse. Together these data suggest that the balance of pro- and anti-inflammatory factors released in response to stress may influence the progress of AA.

Farmacología de la analgesia inducida por el trasplante de médula suprarrenal en el espacio subaracnoideo lumbar de la rata. fundamentos y aproximación clínica / Pharmacology of the analgesia induced by the transplantation of suprarenal medulla to the lumbar subarachnoid space in rats. Foundations and clinical approach

El trasplante de tejido de médula suprarrenal en el espacio subaracnoideo lumbar de la rata es una prometedora herramienta terapéutica para el tratamiento del dolor. El funcionamiento del trasplante se basa en la liberación de péptidos opioides y catecolaminas por parte de las células cromafines en el líquido cefalorraquídeo espinal. Desde ahí estas sustancias pueden ejercer su acción sobre los receptores opioides y adrenérgicos existentes en el asta dorsal de la médula espinal. En algunos casos, el efecto analgésico observado en los tests algesiométricos agudos en la rata ha sido facilitado mediante la estimulación de la liberación de las sustancias neuroactivas con nicotina, mientras que en modelos experimentales de dolor crónico no es necesaria. Este efecto analgésico ha sido antagonizado por naloxona y por fentolamina. En nuestro laboratorio hemos mejorado el efecto analgésico con el tratamiento con amitriptilina y con un inhibidor de la degradación de los péptidos opioides endógenos En clínica se han dado los primeros pasos para la utilización de esta técnica en pacientes con dolor por cáncer terminal. En ellos se han conseguido resultados esperanzadores tanto en el alivio del dolor como en la reducción del tratamiento complementario con opiáceos (AU)

Interacciones de metadona con fármacos antiinfecciosos y sustancias de abuso / Methadone interactions with anti infectious drugs and abuse substances

Frecuentemente es necesario utilizar fármacos antiinfecciosos en pacientes tratados con metadona. Se han observado diversas interacciones entre metadona y fármacos antiinfecciosos , siendo necesaria una especial vigilancia en caso de tratamiento antirretroviral. Se ha descrito aumento de los niveles plasmáticos y de la toxicidad de zidovudina por metadona; también es posible el efecto contrario, es decir la disminución de los efectos del opiáceo por la zidovudina. Entre los inhibidores de la proteasa, ritonavir puede aumentar considerablemente los niveles plasmáticos de metadona y sus efectos depresores. Eritromicina o ketoconazol tienen efectos farmacocinéticos similares. Al contrario, se ha observado el desencadenamiento de síndrome de abstinencia debido a inducción metabólica originada por rifampicina. También las sustancias de abuso, frecuentemente utilizadas por estos pacientes, pueden originar interacciones farmacológicas. La significación clínica de la interacción alcohol/metadona no está clara, en ella pueden participar modificaciones en el metabolismo hepático. A pesar del extenso abuso de cocaína en estos pacientes, son poco conocidas las consecuencias de su consumo con metadona, en las que pudieran estar implicadas interacciones entre la neurotransmisión catecolaminérgica y opioidergica. Se requieren más estudios sobre cannabinoides, anfetaminas o drogas de diseño, de frecuente consumo en esta población (AU)

Effects of stress on susceptibility and severity of inflammation in adjuvant-induced arthritis.

We have utilized the open field and learned helplessness (LH) models of psychological stress to determine whether a differential response to stress can affect the severity of adjuvant-induced arthritis (AA) within a single rat strain. In response to open field stress, the corticosterone response of the low emotivity rats was significantly lower than that of the high emotivity rats. In spite of the differential corticosterone response to stress, no significant difference was found in paw volumes between the AA high and low emotivity groups. In another study, rats were subjected to a learned LH paradigm and separated into two groups based on failed (LH+) or successful (LH-) avoidance. Plasma corticosterone levels in response to avoidable foot shock in the LH- rats were significantly greater than in the LH+ group. Following injection with adjuvant, paw inflammation occurred earlier and was more severe in the LH- rats compared to the LH+ group. These data show that rats with a greater tendency to avoid foot shock have more severe inflammation, despite having a greater corticosterone response to stress. We conclude that an increased corticosterone response to stress does not affect susceptibility to or severity of inflammation in AA. Indeed, in the LH model a more robust response to stress is associated with increased inflammation and earlier onset of the disease.

[Drug interactions of methadone with CNS-active agents]. / Interacciones medicamentosas de metadona con psicofármacos.

Psychoactive medication is frequently used in methadone maintenance treatment programs (MMP) to treat comorbid mental disorders (depression, anxiety, schizophrenia) in opiate-addicts. Thus, several pharmacological interactions are possible. This problem becomes more relevant with the introduction of new CNS-drugs like SSRI, atypical antipsychotics or new anticonvulsants. The most common interactions seen in practice are pharmacodynamic in nature, most often due to the cumulative effects of different drugs on the central nervous system (e.g. neuroleptics or benzodiazepine interactions). However important pharmacokinetic interactions may occur particularly between methadone and antidepressant drugs: Desipramine plasma levels are increased by methadone; further fluvoxamine (and fluoxetine to a less extent) may cause an important increase in serum methadone concentrations. The inhibition of different clusters of the cytochrome P450 system are involved in these interactions. Several lines of evidence suggest that benzodiazepines and methadone may have synergistic interactions and that opiate sedation or respiratory depression could be increased. This is a serious problem, given the widespread use of benzodiazepines among MMP patients. Experimental but not clinical data support methadone and lithium interactions. Finally, classic anticonvulsant drugs, such as phenytoin, carbamazepine and phenobarbital, produce dramatic decreases in methadone levels, which may precipitate a withdrawal syndrome; valproic acid and the new anticonvulsant drugs do not have these effects. Accordingly, caution is advised in the clinical use of methadone when other CNS-drugs are administered.

A differential response to stress is not a prediction of susceptibility or severity in adjuvant-induced arthritis.

It has been suggested that glucocorticoid insufficiency consequent to a blunted hypothalamo-pituitary-adrenal (HPA) axis response to stress may be associated with increased susceptibility to certain experimentally induced autoimmune diseases. We have developed a model which allows this hypothesis to be tested within a single population of rats, using the open field stress. Following the open field stress, rats were divided into groups of high or low emotivity on the basis of faecal pellet count. High and low emotivity groups exhibited significantly elevated plasma corticosterone following the open field stress compared to pre-stress levels, but the corticosterone response of the low emotivity rats was significantly lower than that of the high emotivity rats (p < 0.01). Four hours following termination of the stress, groups of high or low emotivity rats were further divided into two groups and given either an intradermal injection of Mycobacterium butyricum or vehicle for the induction of arthritis. Fourteen days after injection of adjuvant, paw volumes in the arthritic high and low emotivity groups were significantly greater than their respective vehicle-injected non-arthritic controls. However, in spite of the differential corticosterone response to stress, there was no significant difference in paw volumes between the arthritic high and low emotivity groups. These data show that an attenuated response to stress is not associated with enhanced susceptibility to the inflammatory disease of adjuvant-induced arthritis, or with increased severity of inflammation as measured by paw volume on day 14. This experimental paradigm can be more widely applied to extend our observations on the relationship between the HPA axis response to stress and susceptibility to inflammation in other models of experimentally induced autoimmune disease.

Antinociception produced by the peptidase inhibitor, RB 101, in rats with adrenal medullary transplant into the spinal cord.

This study was undertaken to investigate the effects induced by the systemic administration of RB 101 [N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxoprpyl]-L-phenylalanine benzyl ester], a mixed inhibitor of the enkephalin catabolism able to cross the blood-brain barrier, in antinociception produced by adrenal medullary tissue transplanted in the rat spinal subarachnoid space. For this purpose, the antinociceptive responses induced by intravenous (i.v.) administration of RB 101 were evaluated in the tail-flick in rats transplanted 28 and 56 days before the test. Systemic administration of RB 101 induced antinociceptive effects in sham-operated rats, as previously reported. RB 101 also enhanced significantly the antinociception produced by the autotransplant 28 and 56 days after surgery. The antinociceptive responses of RB 101 in both sham-operated and autotransplanted rats were blocked by naloxone, but were not modified by the noradrenergic antagonist, phentolamine, suggesting a selective involvement of opioid mechanisms. The present results indicate that the inhibitors of enkephalin catabolism enhance the antinociception induced by adrenal medullary transplants.

Tramadol induces antidepressant-type effects in mice.

Tramadol is a clinically-effective, centrally-acting analgesic. This drug is a racemic mixture of two enantiomers, each one displaying different mechanisms: (+)tramadol displays opioid agonist properties and inhibits serotonin reuptake while (-)tramadol inhibit preferentially noradrenaline reuptake. The action of tramadol on the monoaminergic reuptake is similar to that of antidepressant drugs. Therefore, we have examined the effects of (+/-)tramadol, (+)tramadol and (-)tramadol in a test predictive of antidepressant activity, the forced swimming test in mice. Both (+/-)tramadol and its (-) enantiomer displayed a dose-dependent reduction on immobility; while the effect induced by the (+) enantiomer was not significant. Inhibition of noradrenaline synthesis, but not of serotonin synthesis, was capable of blocking the effect of (+/-)tramadol. The alpha-adrenoceptor antagonist phentolamine, as well as the alpha2-adrenergic antagonist yohimbine, and the beta-adrenoceptor blocker propranolol countered the immobility-reducing action of (+/-)tramadol. Moreover, neither the serotoninergic blocker methysergide nor the opioid antagonist naloxone antagonized the effect of (+/-)tramadol. Our results show that (+/-)tramadol and (-)tramadol have antidepressant-like effect in mice, probably mediated by the noradrenergic system rather than the serotoninergic or opioidergic ones.

Neonatal handling reduces emotional reactivity and susceptibility to learned helplessness. Involvement of catecholaminergic systems.

Environmental circumstances during the neonatal period are critical for the establishment of adult responses to stressful environmental situations. As these responses are underpinned by adaptations in the functioning of brain neurotransmitter systems, the present study was designed to assess the mediation of noradrenergic and dopaminergic systems in the long-lasting effects of neonatal handling on both emotionality and learned helplessness behaviour. Animals received either prazosin, propranolol, haloperidol or saline before infantile handling. When the animals were 2 months old, they were subjected first to an open field test and then to the learned helplessness paradigm. Non-treated handled animals exhibited lower emotional reactivity and reduced susceptibility to helplessness compared to non-treated non-handled rats. The results suggest that noradrenergic, but not D2-dopamine receptor systems mediate the influence of neonatal handling on the acquisition of learned helplessness in the adult. Only beta-adrenoceptors appear to play a role in emotional responsiveness.

Implication of beta 1- and beta 2-adrenergic receptors in the antinociceptive effect of tricyclic antidepressants.

Tricyclic antidepressants have been shown to be useful for the treatment of pain of varying etiology. Monoaminergic systems seem to be implicated in this phenomenon. In this study, the influence of the selective beta 1- (CGP 20712A) and beta 2- (ICI 118551) adrenergic blockers on the antinociceptive effect of desipramine and nortriptyline was studied in mice using physical and chemical nociceptive tests that implicate different levels of sensory-motor integration in the central nervous system (CNS). An activity test was performed to detect "false positive" or "false negative" results. Results obtained show that both CGP 20712A and ICI 118551 are able to antagonize the antinociceptive effect of these antidepressants in physical tests (hot-plate and tail-flick). However, in chemical tests (acetic acid and formalin), the analgesic effect of the antidepressants used was only antagonized by CGP 20712A. These results suggest that the analgesic effect of desipramine and nortriptyline is mediated by beta-adrenoceptors. The beta-adrenoceptor involved depends on the type of nociceptive stimulus: beta 1 and beta 2 are both implicated when the stimulus is physical, but only beta 1 is involved when the stimulus is chemical.

The effects of different monoaminergic antidepressants on the analgesia induced by spinal cord adrenal medullary transplants in the formalin test in rats.

We studied the effects of chronic intraperitoneal administration of antidepressants on the antinociception induced by adrenal medullary transplants into the subarachnoid space in rats using the formalin test. Administration of drugs started 28 days after operation and the formalin test was performed on Day 56. When amitriptyline (AMT; 15 mg x kg(-1) x day(-1)) was administered to sham-operated rats, it decreased the licking time and increased the transplant-induced analgesia in Phase 1 when administered to transplanted rats. Chronic treatment with fluvoxamine (FVX, 10 mg x kg(-1) x day(-1)) had no influence on the licking response in sham rats, nor did it modify the transplant-induced analgesia when administered to transplanted rats. When desipramine (DMI; 10 mg x kg(-1) x day(-1)) was administered to sham rats, it significantly reduced the licking response in Phase 1, but when administered to transplanted rats it did not increase the transplant-induced analgesia. None of the drugs administered showed any effect on Phase 2 of the formalin test. These results suggest that adrenal medullary transplants into the spinal cord induce analgesia as determined by the formalin test. This effect is more pronounced when AMT (a nonselective noradrenaline-serotonin reuptake inhibitor) is chronically administered, but not when FVX or DMI are chronically administered.

Effect on nociception of intracerebroventricular administration of low doses of neuropeptide Y in mice.

The present study shows further evidence about the implication of neuropeptide Y (NPY) in nociception. The effect of NPY (1-36), when intracerebroventricularly administered, has been studied using two physical models of acute pain (hot plate test and electrical tail stimulation) and the formalin test. The animal response to these three pain models has been shown to be integrated at different levels in the CNS. A decrease in pain threshold was exhibited in both the hot plate test (10, 30, 60, 120 and 480 pmol of NPY i.c.v.) and the electrical tail simulation test (10, 30 and 60 pmol of NPY i.c.v.), while in the formalin test (10, 30, 60 and 120 pmol of NPY icv) the licking response decreased in phase I but not in phase 2. In these three tests NPY showed hyperalgesic or analgesic effects when administered at low doses, while at high doses it failed to induce any effect. Results show that the effect of NPY on nociception is clearly test-dependent and is only observed at low doses.

Attenuation of learned helplessness in rats after transplant of adrenal medulla into the spinal cord.

The influence of an adrenal medullary transplant into the lumbar subarachnoid space on learned helplessness, an animal model of depression, was examined. The transplanted rats were found to be less susceptible than sham-operated animals to become helpless after administration of inescapable shocks. The effect was attributed to release of opioid peptides by chromaffin cells as it was reversed by naloxone. The viability of the transplanted tissue was verified by electron microscopy.

Test-dependent relationship of the antidepressant and analgesic effects of amitriptyline.

Antidepressants have been found to be of value in the treatment of pain of various etiologies. Nevertheless, the data are conflicting as it is often difficult to distinguish between the analgesic and antidepressant action. The analgesic effect of acutely administered amitriptyline at doses of 2.5, 5, 10, 20 and 40 mg/kg was investigated in four nociceptive tests involving physical (hot plate and tail flick tests), or noxious chemical stimuli (acetic acid and formalin tests). Relationships were established between the analgesic actions and the antidepressant effect of acutely administered amitriptyline at doses of 2.5, 5, 10 and 20 mg/kg in the forced swimming test. The results demonstrated a relationship between the antidepressant effect and the analgesic action in the tail flick test, but not in the hot plate, acetic acid and formalin tests. Thus, the type of noxious stimulus may be a determining factor in the relationship between these two pharmacological actions.

Study of the mechanisms involved in behavioral changes induced by flunitrazepam in morphine withdrawal.

1. The attenuation of morphine withdrawal syndrome by acute benzodiazepine administration has been well documented. However, the pharmacological mechanisms implicated in this effect remain unclear. 2. In this study, the possible participation of noradrenergic, serotonergic and benzodiazepine receptors on flunitrazepam-modified morphine withdrawal syndrome was investigated in mice. Flunitrazepam was associated to the noradrenergic antagonists prazosin (1 mg/kg) and propranolol (0.5 mg/kg), the serotonergic agents ritanserine (1 mg/kg) and p-chloro phenylalanine (600 mg/kg), the benzodiazepine antagonist flumazenil (10 mg/kg), and the benzodiazepine partial inverse agonist Ro 15-4513 (5 mg/kg). 3. The decrease in jumping behavior-induced by flunitrazepam was potentiated by prazosin, while ritanserine, flumazenil and Ro 15-4513 blocked this effect. 4. Flunitrazepam-induced increase on wet dog shake frequency was partially reduced by flumazenil, and strongly antagonized by ritanserine and Ro 15-4513. 5. Noradrenergic and serotonergic systems seem to be primarily implicated in the changes induced on jumping and wet dog shakes respectively. These modifications are induced through the activation of the benzodiazepine receptors.

Implication of endogenous opioid system in the learned helplessness model of depression.

The involvement of opioid system on the learned helplessness model of depression was investigated. Animals preexposed to inescapable shocks were treated with either Met-enkephalin, Leu-enkephalin, morphine, imipramine, naloxone, RB 38A (a mixed inhibitor of enkephalin degrading enzymes), or RB 38B (a selective inhibitor of neutral endopeptidase EC 3.4.24.11). Stimulation of opioid system by either opioid agonists or enkephalin catabolism inhibitors reversed the escape deficit induced by shock pretreatment. In contrast, administration of naloxone potentiated the effect of inescapable shocks. Imipramine reduced the number of escape failures in this test, and this effect was antagonized by naloxone. These results point to the involvement of the endogenous opioid system in this model of depression.