Obesogenic Diet-Induced Neuroinflammation: A Pathological Link between Hedonic and Homeostatic Control of Food Intake.

Obesity-induced neuroinflammation is a chronic aseptic central nervous system inflammation that presents systemic characteristics associated with increased pro-inflammatory cytokines such as interleukin 1 beta (IL-1ß) and interleukin 18 (IL-18) and the presence of microglia and reactive astrogliosis as well as the activation of the NLRP3 inflammasome. The obesity pandemic is associated with lifestyle changes, including an excessive intake of obesogenic foods and decreased physical activity. Brain areas such as the lateral hypothalamus (LH), lateral septum (LS), ventral tegmental area (VTA), and nucleus accumbens (NAcc) have been implicated in the homeostatic and hedonic control of feeding in experimental models of diet-induced obesity. In this context, a chronic lipid intake triggers neuroinflammation in several brain regions such as the hypothalamus, hippocampus, and amygdala. This review aims to present the background defining the significant impact of neuroinflammation and how this, when induced by an obesogenic diet, can affect feeding control, triggering metabolic and neurological alterations.

Central and Peripheral Inflammation: A Common Factor Causing Addictive and Neurological Disorders and Aging-Related Pathologies.

Many diseases and degenerative processes affecting the nervous system and peripheral organs trigger the activation of inflammatory cascades. Inflammation can be triggered by different environmental conditions or risk factors, including drug and food addiction, stress, and aging, among others. Several pieces of evidence show that the modern lifestyle and, more recently, the confinement associated with the COVID-19 pandemic have contributed to increasing the incidence of addictive and neuropsychiatric disorders, plus cardiometabolic diseases. Here, we gather evidence on how some of these risk factors are implicated in activating central and peripheral inflammation contributing to some neuropathologies and behaviors associated with poor health. We discuss the current understanding of the cellular and molecular mechanisms involved in the generation of inflammation and how these processes occur in different cells and tissues to promote ill health and diseases. Concomitantly, we discuss how some pathology-associated and addictive behaviors contribute to worsening these inflammation mechanisms, leading to a vicious cycle that promotes disease progression. Finally, we list some drugs targeting inflammation-related pathways that may have beneficial effects on the pathological processes associated with addictive, mental, and cardiometabolic illnesses.

Chronic Exposure to High Fat Diet Affects the Synaptic Transmission That Regulates the Dopamine Release in the Nucleus Accumbens of Adolescent Male Rats.

Obesity is a pandemic caused by many factors, including a chronic excess in hypercaloric and high-palatable food intake. In addition, the global prevalence of obesity has increased in all age categories, such as children, adolescents, and adults. However, at the neurobiological level, how neural circuits regulate the hedonic consumption of food intake and how the reward circuit is modified under hypercaloric diet consumption are still being unraveled. We aimed to determine the molecular and functional changes of dopaminergic and glutamatergic modulation of nucleus accumbens (NAcc) in male rats exposed to chronic consumption of a high-fat diet (HFD). Male Sprague-Dawley rats were fed a chow diet or HFD from postnatal day (PND) 21 to 62, increasing obesity markers. In addition, in HFD rats, the frequency but not amplitude of the spontaneous excitatory postsynaptic current is increased in NAcc medium spiny neurons (MSNs). Moreover, only MSNs expressing dopamine (DA) receptor type 2 (D2) increase the amplitude and glutamate release in response to amphetamine, downregulating the indirect pathway. Furthermore, NAcc gene expression of inflammasome components is increased by chronic exposure to HFD. At the neurochemical level, DOPAC content and tonic dopamine (DA) release are reduced in NAcc, while phasic DA release is increased in HFD-fed rats. In conclusion, our model of childhood and adolescent obesity functionally affects the NAcc, a brain nucleus involved in the hedonic control of feeding, which might trigger addictive-like behaviors for obesogenic foods and, through positive feedback, maintain the obese phenotype.

Enhanced Astrocyte Activity and Excitatory Synaptic Function in the Hippocampus of Pentylenetetrazole Kindling Model of Epilepsy.

Epilepsy is a chronic condition characterized by recurrent spontaneous seizures. The interaction between astrocytes and neurons has been suggested to play a role in the abnormal neuronal activity observed in epilepsy. However, the exact way astrocytes influence neuronal activity in the epileptogenic brain remains unclear. Here, using the PTZ-induced kindling mouse model, we evaluated the interaction between astrocyte and synaptic function by measuring astrocytic Ca2+ activity, neuronal excitability, and the excitatory/inhibitory balance in the hippocampus. Compared to control mice, hippocampal slices from PTZ-kindled mice displayed an increase in glial fibrillary acidic protein (GFAP) levels and an abnormal pattern of intracellular Ca2+-oscillations, characterized by an increased frequency of prolonged spontaneous transients. PTZ-kindled hippocampal slices also showed an increase in the E/I ratio towards excitation, likely resulting from an augmented release probability of excitatory inputs without affecting inhibitory synapses. Notably, the alterations in the release probability seen in PTZ-kindled slices can be recovered by reducing astrocyte hyperactivity with the reversible toxin fluorocitrate. This suggests that astroglial hyper-reactivity enhances excitatory synaptic transmission, thereby impacting the E/I balance in the hippocampus. Altogether, our findings support the notion that abnormal astrocyte-neuron interactions are pivotal mechanisms in epileptogenesis.

Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels.

The misuse of psychostimulants is an increasing behavior among young people, highlighting in some countries the abuse of modafinil (MOD) as a neuropotentiator. However, several clinical trials are investigating MOD as an alternative pharmacological treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. On the other hand, the early use of psychostimulants and the misdiagnosis rates in ADHD make it crucial to investigate the brain effects of this type of drug in young healthy individuals. The aim of this work was to evaluate the effects of chronic MOD treatment on neurochemicals (γ-aminobutyric acid and glutamate), dopamine receptor 2 (D2) expression and behavior (non-selective attention "NSA") in the mesocorticolimbic system of young healthy Sprague-Dawley rats. Preadolescent male rats were injected with MOD (75 mg/kg, i.p.) or a vehicle for 14 days (from postnatal day 22 to 35). At postnatal day 36, we measured the GLU and GABA contents and their extracellular levels in the nucleus accumbens (NAc). In addition, the GLU and GABA contents were measured in the ventral tegmental area (VTA) and D2 protein levels in the prefrontal cortex (PFC). Chronic use of MOD during adolescence induces behavioral and neurochemical changes associated with the mesocorticolimbic system, such as a reduction in PFC D2 expression, VTA GABA levels and NSA. These results contribute to the understanding of the neurological effects of chronic MOD use on a young healthy brain.

The Role of the Paraventricular-Coerulear Network on the Programming of Hypertension by Prenatal Undernutrition.

A crucial etiological component in fetal programming is early nutrition. Indeed, early undernutrition may cause a chronic increase in blood pressure and cardiovascular diseases, including stroke and heart failure. In this regard, current evidence has sustained several pathological mechanisms involving changes in central and peripheral targets. In the present review, we summarize the neuroendocrine and neuroplastic modifications that underlie maladaptive mechanisms related to chronic hypertension programming after early undernutrition. First, we analyzed the role of glucocorticoids on the mechanism of long-term programming of hypertension. Secondly, we discussed the pathological plastic changes at the paraventricular nucleus of the hypothalamus that contribute to the development of chronic hypertension in animal models of prenatal undernutrition, dissecting the neural network that reciprocally communicates this nucleus with the locus coeruleus. Finally, we propose an integrated and updated view of the main neuroendocrine and central circuital alterations that support the occurrence of chronic increases of blood pressure in prenatally undernourished animals.

Effects of Early Life Exposure to Sex Hormones on Neurochemical and Behavioral Responses to Psychostimulants in Adulthood: Implications in Drug Addiction.

Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.

Vasopressin in the lateral septum decreases conditioned place preference to amphetamine and nucleus accumbens dopamine release.

The lateral septum (LS) is a limbic nucleus interconnected with several brain areas involved in the regulation of mood and reward. Vasopressin (AVP) is a neuropeptide that has been related to the effects of drugs of abuse, but its role in the addictive process is poorly understood. LS expresses a high density of AVP 1A receptors (V1A ). The aim of this work was to examine whether the modulation of LS AVP system affects the behavioral and neurochemical responses to amphetamine (AMPH) in male rats. Our results show that AMPH-induced conditioned place preference (CPP) produces a decrease in LS AVP content. Besides, we demonstrate that the microinjection of AVP in the LS impairs the expression of AMPH-induced CPP and that this effect is mediated by the activation of the V1A receptor in the LS. AVP microinjection in the LS elicited a decrease in neuronal activity in the nucleus accumbens (NAc) in animals subjected to AMPH conditioning. Finally, AVP microinjection in the LS decreased dopamine (DA) release in the NAc. Overall, our data demonstrate that intra-LS AVP diminishes the expression of AMPH conditioning behavior while decreasing neuronal activity and DA release in the NAc. Presumably, the effects of AVP in the LS produce an inhibition of GABAergic projections to the VTA, increasing local inhibitory tone in this nucleus, which in turn reduces the activity of DA projections to NAc. Thus, these results contribute to the knowledge about the role of AVP in LS in regulating the reward circuit and addictive like behaviors.

Pre- and postnatal alcohol exposure delays, in female but not in male rats, the extinction of an auditory fear conditioned memory and increases alcohol consumption.

Repeated exposure to alcohol increases retrieval of fear-conditioned memories, which facilitates, among other factors, the emergence of post-traumatic stress disorder (PTSD). Individuals with PTSD are more likely to develop alcohol and substance abuse related disorders. We assessed if prenatal and early postnatal alcohol exposure (PAE) increased the susceptibility to retain aversive memories and if this was associated with subsequent heightened alcohol consumption. Pregnant Sprague-Dawley rats were exposed for 22 hr/day, throughout pregnancy and until postnatal Day 7 to a single bottle of sucralose - sweetened 10% alcohol solution (PAE Group), or to a single bottle of tap water and sucralose (Control Group). Auditory fear conditioning (AFC) was performed in the adolescent offspring at postnatal Day 40. Freezing was measured during acquisition, retention and extinction phases, followed by 3 weeks of free choice alcohol intake. Female, but not male, PAE rats exhibited impaired extinction of the aversive memory, a finding associated with higher levels of 3-4 Dihidroxyphenylacetic acid (DOPAC) in the nucleus accumbens and heightened alcohol intake, respect to controls. These findings suggest that PAE makes females more vulnerable to long-term retention of aversive memories, which coexist with heightened alcohol intake. These findings are reminiscent of those of PTSD.

Pharmacological Characterization of 4-Methylthioamphetamine Derivatives.

Amphetamine derivatives have been used in a wide variety of pathologies because of their pharmacological properties as psychostimulants, entactogens, anorectics, and antidepressants. However, adverse cardiovascular effects (sympathomimetics) and substance abuse problems (psychotropic and hallucinogenic effects) have limited their use. 4-Methylthioamphetamine (MTA) is an amphetamine derivative that has shown to inhibit monoamine uptake and monoamine oxidase. However, the pharmacological characterization (neurochemical, behavioral, and safety) of its derivatives 4-ethylthioamphetamine (ETA) and 4-methylthio-phenil-2-butanamine (MT-But) have not been studied. In the current experiments, we show that ETA and MT-But do not increase locomotor activity and conditioned place preference with respect to MTA. At the neurochemical level, ETA and MT-But do not increase in vivo DA release in striatum, but ETA and MT-But affect the nucleus accumbens bioaccumulation of DA and DOPAC. Regarding cardiovascular effects, the administration of MTA and ETA increased the mean arterial pressure and only ETA significantly increases the heart rate. Our results show that the pharmacological and safety profiles of MTA are modulated by changing the methyl-thio group or the methyl group of the aminoethyl chain.

Nicotinic Antagonist UFR2709 Inhibits Nicotine Reward and Decreases Anxiety in Zebrafish.

Zebrafish is becoming a popular animal model in neuropharmacology and drug discovery, mainly due to its ease of handling and low costs involved in maintenance and experimental work. This animal displays a series of complex behaviours that makes it useful for assessing the effects of psychoactive drugs. Here, adult zebrafish were used for assessment of the anxiolytic and anti-addictive properties of UFR2709, a nicotinic receptor (nAChR) antagonist, using two behavioural paradigms to test for addiction, the novel tank diving test to assess anxiety and the conditioned place preference (CPP). Furthermore, the expression of nAChR subunits α4 and α7 was measured in the zebrafish brain. The results show that UFR2709 exhibits an anxiolytic effect on zebrafish and blocks the effect evoked by nicotine on CPP. Moreover, UFR2709 significantly decreased the expression of α4 nicotinic receptor subunit. This indicates that UFR2709 might be a useful drug for the treatment of nicotine addiction.

Proteostasis and Mitochondrial Role on Psychiatric and Neurodegenerative Disorders: Current Perspectives.

Proteostasis involves processes that are fundamental for neural viability. Thus, protein misfolding and the formation of toxic aggregates at neural level, secondary to dysregulation of the conservative mechanisms of proteostasis, are associated with several neuropsychiatric conditions. It has been observed that impaired mitochondrial function due to a dysregulated proteostasis control system, that is, ubiquitin-proteasome system and chaperones, could also have effects on neurodegenerative disorders. We aimed to critically analyze the available findings regarding the neurobiological implications of proteostasis on the development of neurodegenerative and psychiatric diseases, considering the mitochondrial role. Proteostasis alterations in the prefrontal cortex implicate proteome instability and accumulation of misfolded proteins. Altered mitochondrial dynamics, especially in proteostasis processes, could impede the normal compensatory mechanisms against cell damage. Thereby, altered mitochondrial functions on regulatory modulation of dendritic development, neuroinflammation, and respiratory function may underlie the development of some psychiatric conditions, such as schizophrenia, being influenced by a genetic background. It is expected that with the increasing evidence about proteostasis in neuropsychiatric disorders, new therapeutic alternatives will emerge.

Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats.

We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 µL); DHT (dihydrotestosterone of 1.0 mg/50 µL); EV (estradiol valerate of 0.1 mg/50 µL); and control (sesame oil of 50 µL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.

"How and when Chilean Pharmacology started to be experimental and became a science".

Pharmacology in Chile has about 75 years of history and from its beginning until today has grown exponentially. Today, pharmacology is taught in the biomedical careers of the main Chilean universities and research centers in pharmacology are in the north, central and south of Chile. This editorial offers an overview of the main milestones that have led to the consolidation of Chilean pharmacology in Latin America and the world.

Exposure to repeated immobilization stress inhibits cocaine-induced increase in dopamine extracellular levels in the rat ventral tegmental area.

A higher vulnerability to drug abuse has been observed in human studies of individuals exposed to chronic or persistent stress, as well as in animal models of drug abuse. Here, we explored the effect of repeated immobilization stress on cocaine-induced increase in dopamine extracellular levels in VTA and its regulation by corticotropin-releasing factor (CRF) and GABA systems. Cocaine (10mg/Kg i.p.) induced an increase of VTA DA extracellular levels in control rats. However, this effect was not observed in repeated stress rats. Considering the evidence relating stress with CRF, we decided to perfuse CRF and CP-154526 (selective antagonist of CRF1 receptor) in the VTA of control and repeated stress rats, respectively. We observed that perfusion of 20µM CRF inhibited the increase of VTA DA extracellular levels induced by cocaine in control rats. Interestingly, we observed that in the presence of 10µM CP-154526, cocaine induced a significant increase of VTA DA extracellular levels in repeated stress rats. Regarding the role of VTA GABA neurotransmission, cocaine administration induced a significant increase in VTA GABA extracellular levels only in repeated stress rats. Consistently, cocaine was able to increase VTA DA extracellular levels in repeated stress rats when 100µM bicuculline, an antagonist of GABAA receptor, was perfused intra VTA. Thus, both CRF and GABA systems are involved in the lack of response to cocaine in the VTA of repeated stress rats. It is tempting to suggest that the loss of response in VTA dopaminergic neurons to cocaine, after repeated stress, is due to an interaction between CRF and GABA systems.

Withdrawal from chronic amphetamine reduces dopamine transmission in the rat lateral septum.

The lateral septum (LS) is a brain nucleus implicated in the addictive process. This study investigated whether withdrawal from chronic amphetamine (AMPH) induces alterations in dopamine (DA) transmission within the LS. Male Sprague-Dawley rats were injected with AMPH (2.5 mg/kg i.p.) or saline during 14 days and thereafter subjected to 24 hr or 14 days of withdrawal. After these withdrawal periods, we measured DA extracellular levels by in vivo microdialysis, DA tissue levels, and tyrosine hydroxylase (TH) and vesicular monoamine transporter-2 (VMAT2) expression in the LS. Our results showed a significant decrease in K(+) -induced release of DA in the LS of AMPH-treated rats, 14 days after withdrawal compared with saline-treated rats. There were no significant differences in DA tissue content and TH expression. Interestingly, there was a decrease of LS VMAT2 expression in AMPH-treated rats, 14 days after withdrawal compared with saline-treated rats. This is the first neurochemical evidence showing that withdrawal from repeated AMPH administration decreases K(+) -induced DA release in the rat LS. Our results suggest that this decrease in DA releasability could be due to a decrease in DA vesicular uptake. The possibility that these neurochemical changes are associated with AMPH abstinence syndrome should be further explored.

Glucagon Increases Retinal Rod Bipolar Cell Inhibition Through a D1 Dopamine Receptor-Dependent Pathway That Is Altered After Lens-Defocus Treatment in Mice.

Purpose: Members of the secretin/glucagon family have diverse roles in retinal physiological and pathological conditions. Out of them, glucagon has been associated with eye growth regulation and image defocus signaling in the eye, both processes central in myopia induction. On the other hand, dopamine is perhaps the most studied molecule in myopia and has been proposed as fundamental in myopia pathogenesis. However, glucagonergic activity in the mammalian retina and its possible link with dopaminergic signaling remain unknown. Methods: To corroborate whether glucagon and dopamine participate together in the modulation of synaptic activity in the retina, inhibitory post-synaptic currents were measured in rod bipolar cells from retinal slices of wild type and negative lens-exposed mice, using whole cell patch-clamp recordings and selective pharmacology. Results: Glucagon produced an increase of inhibitory post-synaptic current frequency in rod bipolar cells, which was also dependent on dopaminergic activity, as it was abolished by dopamine type 1 receptor antagonism and under scotopic conditions. The effect was also abolished after 3-week negative lens-exposure but could be recovered using dopamine type 1 receptor agonism. Conclusions: Altogether, these results support a possible neuromodulatory role of glucagon in the retina of mammals as part of a dopaminergic activity-dependent synaptic pathway that is affected under myopia-inducing conditions.

Early-life exposure to sex hormones promotes voluntary ethanol intake in adulthood. A vulnerability factor to drug addiction.

While there is extensive research on alcohol dependence, the factors that make an individual vulnerable to developing alcoholism haven't been explored much. In this study, we aim to investigate how neonatal exposure to sex hormones affects alcohol intake and the regulation of the mesolimbic pathway in adulthood. The study aimed to investigate the impact of neonatal exposure to a single dose of testosterone propionate (TP) or estradiol valerate (EV) on ethanol consumption in adult rats. The rats were subjected to a two-bottle free-choice paradigm, and the content of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens (NAcc) was measured using HPLC-ED. The expression of critical DA-related proteins in the mesolimbic pathway was evaluated through RT-qPCR and western blot analysis. Supraphysiological neonatal exposure to EV or TP resulted in increased ethanol intake over four weeks in adulthood. In addition, the DA and DOPAC content was reduced and increased in the NAcc of EV and TP-treated rats, and ß-endorphin content in the hypothalamus decreased in EV-treated rats. The VTA µ receptor and DA type 2 form short receptor (D2S) expression were significantly reduced in EV and TP male rats. Finally, in an extended 6-week protocol, the increase in ethanol consumption induced by EV was mitigated during the initial two hours post-naloxone injection. Neonatal exposure to sex hormones is a detrimental stimulus for the brain, which can facilitate the development of addictive behaviors, including alcohol use disorder.

Risperidone in analgesia induced by paracetamol and meloxicam in experimental pain.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the best therapeutic options to treat pain. Their use in combination with other drugs may broaden their applicability in analgesia if their ceiling and adverse effects are reduced. The aim of this study was to evaluate the pharmacological interaction of two NSAIDs, paracetamol and meloxicam, with the antipsychotic drug risperidone in mice, in several experimental tests of nociceptive and inflammatory pain. Antinociception was assessed by dose-response curves to paracetamol and meloxicam before and after the i.p. administration of 0.5 mg/kg of risperidone. Results are presented as means ± SEM and differences were calculated by one-way ANOVA followed by Tukey's post-test. Paracetamol and meloxicam produced a dose-related antinociceptive effect with diverse potencies. Risperidone increased the analgesia mediated by paracetamol and meloxicam only in the tonic tests that detected inflammatory pain. This suggests that COX inhibition is only a partial explanation of the increased analgesic potency of paracetamol and meloxicam since the effects of NSAIDs in the CNS are mediated by multiple mechanisms. These results indicate that the combination of risperidone with paracetamol or meloxicam could be a new and effective alternative for the management of inflammatory pain.