J.A. Micó

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.

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.

Evaluation of milnacipran, in comparison with amitriptyline, on cold and mechanical allodynia in a rat model of neuropathic pain

Milnacipran, a serotonin/norepinephrine reuptake inhibitor (SNRI), has shown efficacy against several chronic pain conditions, including fibromyalgia. Here, we evaluated, in rats, its anti-allodynic effects following acute or sub-chronic treatment in a model of neuropathic pain (chronic constriction injury, CCI, of the sciatic nerve). Amitriptyline, a tricyclic antidepressant active pre-clinically and clinically against neuropathic pains, was added as a comparison compound. Upon acute i.p. administration, milnacipran was potently efficacious in the CCI model. It significantly reduced thermal allodynia in the cold (4°C) plate test (MED=2.5mg/kg), and attenuated mechanical allodynia in the von Frey filaments test (MED=10mg/kg). Given sub-chronically (7day, b.i.d.), milnacipran was effective at 10mg/kgi.p. in both tests. Acute amitriptyline (10mg/kgi.p.) was efficacious against mechanical, but less so against cold allodynia; under sub-chronic conditions, it was only active against mechanical allodynia. These data show that milnacipran is as efficacious as the reference compound amitriptyline in a pre-clinical model of injury-induced neuropathy, and demonstrate for the first time that it is active acutely and sub-chronically against cold allodynia. They also suggest that milnacipran has the potential to alleviate allodynia associated with nerve compression-induced neuropathic pain in the clinic (for example following discal hernia, avulsion or cancer-induced tissue damage).

Age-dependence of Schneiderian psychotic symptoms in bipolar patients.

Psychotic symptoms frequently occur in bipolar disorder, especially in younger patients. However, whether the association with younger age also extends to psychotic symptoms that have traditionally been associated with schizophrenia, such as Schneiderian first-rank symptoms (FRSs), is unclear. This study examined FRSs in bipolar I patients and their relationship to age and gender. The sample comprised 103 consecutive inpatients who met DSM IV criteria for bipolar disorder, manic or mixed. FRSs were rated with the Scale for the Assessment of Positive Symptoms (SAPS). Interaction between FRSs and gender and FRSs and age was assessed using logistic regression. A high rate of FRSs in manic and mixed patients was found with a higher frequency in men (31%) than in women (14%; P=0.038). A monotonic increase in the association between FRSs and younger age was apparent (odds ratios (OR) over five levels: 1.42; 1.00-2.01). These results confirm previous findings that FRSs are not specific to schizophrenia and suggest in addition that a dimension of nuclear psychotic experiences of developmental origin extends across categorically defined psychotic disorders.

Cooperative opioid and serotonergic mechanisms generate superior antidepressant-like effects in a mice model of depression.

Although complete remission of symptoms is the goal of any depression treatment, many patients fail to attain or maintain a long-term, symptom-free status. The opioid system has been implicated in the aetiology of depression, and some preclinical and clinical data suggest that opioids possess a genuine antidepressant-like effect. This study aimed to investigate a potential antidepressant strategy combining different classes of monoaminergic compounds with the weak mu-opioid agonist codeine in the tail suspension test in mice, a paradigm aimed at screening potential antidepressants. The results showed that codeine produced an antidepressant-like effect when administered alone, that was effectively antagonized by the opioid antagonist naloxone. The combination of subeffective doses of codeine with the selective serotonin reuptake inhibitors (fluoxetine or citalopram) lead to an accentuated reduction in immobility time. In contrast, immobility time remained unchanged when codeine was combined with a noradrenaline reuptake inhibitor (desipramine) or with a noradrenaline/serotonin reuptake inhibitor (duloxetine). The immobility time also remained unchanged with the combination of subeffective doses of codeine plus (+/-)-tramadol (weak mu-opioid agonist with serotonin/noradrenaline reuptake inhibitor properties) or (-)-tramadol (noradrenaline reuptake inhibitor). Conversely, the combination with (+)-tramadol (mu-opioid agonist with serotonin reuptake inhibitor properties) produced a large decrease in the immobility time. All these combinations were without effects on motor behaviour in mice. These data support the hypothesis that a combination of classical serotonergic antidepressants and weak opioid receptor agonists may be a helpful new strategy in the treatment of refractory depression.

Elucidating the Mechanism of Action of Pregabalin

This review provides a brief summary of what is known about the anxiolytic mechanism of action of pregabalin, a highly selective, high-affinity ligand of the P/Q type of voltage-gated calcium channel (CaV). Evidence from in vivo models of neuronal hyperexcitability suggests that pregabalin reduces synaptic release of neurotransmitters in selected CNS regions including the cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum and dorsal horn of the spinal cord. Release of neurotransmitters from the synaptic vesicle, and propagation of neurotransmission, requires the vesicle to fuse with the presynaptic membrane. Pregabalin binding to the α2δ type 1 protein of the P/Q type CaV reduces the availability of Ca2+ required for membrane fusion and exocytosis of neurotransmitters. Evidence that the anxiolytic mechanism of action of pregabalin is mediated by binding to the α2δ type 1 protein comes from animal models, which have demonstrated a structure-activity relationship between the affinity of ligands for the α2δ type 1 protein and their potency in models of anxiety such as the Vogel conflict test. Furthermore, the anxiolytic activity of pregabalin is lost in transgenic mice with specific point mutations in the CaV α2δ type 1 protein. Pregabalin-mediated reduction in calcium currents has also been shown to result in a significant inhibition of the release of neurotransmitters implicated in pa-thological anxiety such as glutamate and monoamine neurotransmitters. However, further research is needed to confirm that these effects contribute to the anxiolytic mechanism of action of pregabalin. Finally, pregabalin may also act by inhibiting synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of CaV to the plasma membrane.

The role of age in the development of Schneiderian symptoms in patients with a first psychotic episode

Objective:  The likelihood of developing psychotic symptoms greatly increases after puberty. In acute psychotic disorders, first rank symptoms (FRS) are prevalent and considered useful for the diagnostic process. The aim of this study was to test for a linear association between age and the probability of occurrence of FRS in patients with a first psychotic episode (FPE).

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.

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

Highlights • Paracetamol has an antinociceptive action in the formalin test.• 5-HT1A and 5-HT1B receptors seem to be involved in the antinociceptive effect of paracetamol.• 5-HT1A/B antagonists could improve the antinociceptive effect of paracetamol.

JS01-01 - Psychotropic drugs and chronic pain

Introduction Pain complaints are frequent in psychiatric and primary care settings. Furthermore, in pain clinic, depression and pain disorders are common comorbidities. On the other hand, several antidepressants are effective in the management of chronic pain and in alleviating pain complaints in depressed patients. Objectives In this lecture, we summarize the current knowledge with regard to the use of antidepressants in chronic pain conditions and in pain as a somatic complaint in depression. We review the pharmacological mechanisms and the neurobiological substrate of these properties. Aims To give arguments for the recognition of antidepressants as useful tool to treat pain in depression and depression in chronic pain patients, and to provide information about the right choice of an antidepressant in chronic pain. Conclusion The monoaminergic system participates both in the regulation of mood and in the modulation of pain. Antidepressants have several properties modulating monoamines. Some of these properties are critical to understand the mechanisms of action of these compounds in chronic pain and in alleviating pain as a somatic symptom in depressed patients. The discussion about whether antidepressants alleviate pain acting on mood or pain transmission is a matter open to discussion, however there is no doubt about the utility of these drugs in pain. Recent studies in modified genetic animals reinforce the idea the not only monoamines but also other neurotransmission systems underlie these effects.