An evaluation of immune function and effects of fluoxetine in rodent models of depressive and sickness behavior

Several lines of research have identified similarities between behaviors associated with major depressive disorder (MDD) and those associated with immune activation, referred to as sickness behaviors. Reports of altered immune parameters in MDD patients further point to a shared mechanism underlying depressive and sickness behaviors. Most reliable of these immune changes are suppressed natural killer cell activity (NKCA) and alterations in leukocyte subsets. Further, some studies have demonstrated that treatment of MDD with the selective serotonergic reuptake inhibitors (SSRIs) increase NKCA in a subset of depressed patients. In light of these findings the following questions were posed: (1) Is sickness behavior induced by animal models of depressive states? (2) Is NKCA suppression observed in rodent models of MDD, and is this reduction reversible by SSRI administration? (3) Does repeated immune activation induce depressive behaviors and the immune alterations observed in MDD patients, and does SSRI administration restore these alterations? Behavioral similarities between depressive and sickness behaviors, and immune alterations associated with MDD suggest that immune activation leads to depressive behaviors. The immune alterations found with MDD are also associated with the release of proinflammatory cytokines from activated macrophages which have been implicated in sickness behavior and hypothalamic-pituitary-adrenal (HPA) axis activation. Administration of proinflammatory mediators to non-depressed patients induces depressive symptoms and increases HPA axis activity. HPA axis activation is associated with MDD and is modulated by SSRIs. Further, SSRIs have been shown to suppress macrophage function. Chronic mild stress (CMS) in rodents is used to model MDD, and elicits depressive behaviors and increases HPA axis activity. With the questions above, the following hypotheses were tested: (1) CMS and repeated immune activation with zymosan (yeast cell wall mannoprotein) will have similar and parallel effects on depressive behaviors measured in Porsolt\u27s forced swim test and on sickness behaviors defined by the social investigation task; (2) Both CMS and repeated immune activation will activate the HPA axis evidenced by elevated circulating corticosterone; (3) Both CMS and repeated immune activation will disrupt innate immune function measured by decreased NKCA and macrophage activation evidenced by increased intracellular ROS; and (4) chronic fluoxetine will normalize behavior, endocrine, and immune responses. CMS suppressed NKCA, and consistent with findings in MDD patients, chronic fluoxetine abrogated CMS-induced suppression of NKCA. Furthermore, CMS stimulated macrophage activity as evidenced by increased ROS, which was not altered by fluoxetine. Taken together these findings suggest that the CMS model is an appropriate model to further explore the relationship between depressive behaviors and related immune function. In contrast, chronic zymosan did not alter immune measures. Both CMS and chronic zymosan induced depressive behaviors, however neither manipulation induced sickness behavior. While previous studies have evaluated acute pathogen administration, given the chronic nature of MDD, the current study used repeated administration of pathogen. This may account for the differences with previous research. FLX did not reverse behavior alterations induced by chronic zymosan

An evaluation of immune function and effects of fluoxetine in rodent models of depressive and sickness behavior

Several lines of research have identified similarities between behaviors associated with major depressive disorder (MDD) and those associated with immune activation, referred to as sickness behaviors. Reports of altered immune parameters in MDD patients further point to a shared mechanism underlying depressive and sickness behaviors. Most reliable of these immune changes are suppressed natural killer cell activity (NKCA) and alterations in leukocyte subsets. Further, some studies have demonstrated that treatment of MDD with the selective serotonergic reuptake inhibitors (SSRIs) increase NKCA in a subset of depressed patients. In light of these findings the following questions were posed: (1) Is sickness behavior induced by animal models of depressive states? (2) Is NKCA suppression observed in rodent models of MDD, and is this reduction reversible by SSRI administration? (3) Does repeated immune activation induce depressive behaviors and the immune alterations observed in MDD patients, and does SSRI administration restore these alterations? Behavioral similarities between depressive and sickness behaviors, and immune alterations associated with MDD suggest that immune activation leads to depressive behaviors. The immune alterations found with MDD are also associated with the release of proinflammatory cytokines from activated macrophages which have been implicated in sickness behavior and hypothalamic-pituitary-adrenal (HPA) axis activation. Administration of proinflammatory mediators to non-depressed patients induces depressive symptoms and increases HPA axis activity. HPA axis activation is associated with MDD and is modulated by SSRIs. Further, SSRIs have been shown to suppress macrophage function. Chronic mild stress (CMS) in rodents is used to model MDD, and elicits depressive behaviors and increases HPA axis activity. With the questions above, the following hypotheses were tested: (1) CMS and repeated immune activation with zymosan (yeast cell wall mannoprotein) will have similar and parallel effects on depressive behaviors measured in Porsolt\u27s forced swim test and on sickness behaviors defined by the social investigation task; (2) Both CMS and repeated immune activation will activate the HPA axis evidenced by elevated circulating corticosterone; (3) Both CMS and repeated immune activation will disrupt innate immune function measured by decreased NKCA and macrophage activation evidenced by increased intracellular ROS; and (4) chronic fluoxetine will normalize behavior, endocrine, and immune responses. CMS suppressed NKCA, and consistent with findings in MDD patients, chronic fluoxetine abrogated CMS-induced suppression of NKCA. Furthermore, CMS stimulated macrophage activity as evidenced by increased ROS, which was not altered by fluoxetine. Taken together these findings suggest that the CMS model is an appropriate model to further explore the relationship between depressive behaviors and related immune function. In contrast, chronic zymosan did not alter immune measures. Both CMS and chronic zymosan induced depressive behaviors, however neither manipulation induced sickness behavior. While previous studies have evaluated acute pathogen administration, given the chronic nature of MDD, the current study used repeated administration of pathogen. This may account for the differences with previous research. FLX did not reverse behavior alterations induced by chronic zymosan

Snake venom components enhance pain upon subcutaneous injection: an initial examination of spinal cord mediators

Snakebites are a relevant public health problem in Central and South America. Snake bite envenomations cause intense pain, not relieved by anti-venom. The fangs of many species are short, causing subcutaneous injection. Fangs of larger species inflict subcutaneous or intramuscular envenomation. To understand pain induced by subcutaneous venom, this study examined spinal mechanisms involved in pain-enhancing effects of subcutaneous Lys49 and Asp49 secretory phospholipase-A2 (sPLA2), two components of Bothrops asper snake venom showing highly different enzymatic activities. Unilateral intraplantar sPLA2-Lys49 (catalytically inactive) or sPLA2-Asp49 (catalytically active) into rat hindpaws each induced mechanical hyperalgesia (Randall–Selitto test), whereas only catalytically active sPLA2-Asp49 caused mechanical allodynia (von Frey test). Effects induced by both sPLA2s were inhibited by intrathecal fluorocitrate, a reversible glial metabolic inhibitor. In support, immunohistochemical analysis revealed activation of dorsal horn astrocytes and microglia after intraplantar injection of either sPLA2. Spinal proinflammatory cytokines, nitric oxide, and prostanoids each appear to be involved in the pain-enhancing effects of these sPLA2s. Blockade of interleukin-1 (IL1) inhibited hyperalgesia induced by both sPLA2s, while leaving allodynia unaffected. Blockade of tumor necrosis factor reduced responses to sPLA2-Asp49. An inhibitor of neuronal nitric oxide synthase, 7-nitroindazole (7-NI), inhibited hyperalgesia induced by both sPLA2s, without interfering with allodynia induced by sPLA2-Asp49. On the other hand, l-N6-(1-iminoethyl)lysine (l-NI), an inhibitor of the inducible nitric oxide synthase, did not alter any sPLA2-induced effect. Lastly, celecoxib, an inhibitor of cyclooxygenase-2, attenuated sPLA2 actions. These data provide the first evidence of spinal mediators involved in pain facilitation induced by subcutaneous venoms.International Association for the Study of Pain//IASP/Estados UnidosCoordenação de Aperfeiçoamento de Pessoal de Nível Superior/[0596/02-7]/CAPES/BrasilConselho Nacional de Desenvolvimento Científico e Tecnológico//CNPq/BrasilFundação de Amparo à Pesquisa do Estado de São Paulo/[99/08432-8]/FAPESP/BrasilFundação de Amparo à Pesquisa do Estado de São Paulo/[00/12303-8]/FAPESP/BrasilUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Snake venom phospholipase A2s (Asp49 and Lys49) induce mechanical allodynia upon peri-sciatic administration: involvement of spinal cord glia, proinflammatory cytokines and nitric oxide

Snakebites constitute a serious public health problem in Central and South America, where species of the lancehead pit vipers (genus Bothrops) cause the majority of accidents. Bothrops envenomations are very painful, and this effect is not neutralized by antivenom treatment. Two variants of secretory phospholipases A2 (sPLA2), corresponding to Asp49 and Lys49 PLA2s, have been isolated from Bothrops asper venom. These sPLA2s induce hyperalgesia in rats following subcutaneous injection. However, venom in natural Bothrops bites is frequently delivered intramuscularly, thereby potentially reaching peripheral nerve bundles. Thus, the present series of experiments tested whether these sPLA2s could exert pain-enhancing effects following administration around healthy sciatic nerve. Both were found to produce mechanical allodynia ipsilateral to the injection site; no thermal hyperalgesia was observed. As no prior study has examined potential spinal mechanisms underlying sPLA2 actions, a series of anatomical and pharmacological studies were performed. These demonstrated that both sPLA2s produce activation of dorsal horn astrocytes and microglia that is more prominent ipsilateral to the site of injection. As proinflammatory cytokines and nitric oxide have each been previously implicated in spinally mediated pain facilitation, the effect of pharmacological blockade of these substances was tested. The results demonstrate that mechanical allodynia induced by both sPLA2s is blocked by interleukin-1 receptor antagonist, anti-rat interleukin-6 neutralizing antibody, the anti-inflammatory cytokine interleukin-10, and a nitric oxide synthesis inhibitor (l-NAME). As a variety of immune cells also produce and release sPLA2s during inflammatory states, the data may have general implications for the understanding of inflammatory pain.International Association for the Study of Pain//IASP/Estados UnidosCoordenação de Aperfeiçoamento de Pessoal de nivel Superior/[BEX0596/02-7]/CAPES/BrasilFundação de Amparo à Pesquisa do Estado de São Paulo/[99/08432-8]/FAPESP/BrasilNational Institutes of Health/[DA015642]/NIH/Estados UnidosNational Institutes of Health/[NS40696]/NIH/Estados UnidosNational Institutes of Health/[NS38020]/NIH/Estados UnidosNational Institutes of Health/[DA015656]/NIH/Estados UnidosNational Institutes of Health/[AI51093]/NIH/Estados UnidosUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP

Glia as the "bad guys": Implications for improving clinical pain control and the clinical utility of opioids

Within the past decade, there has been increasing recognition that glia are far more than simply “housekeepers” for neurons. This review explores two recently recognized roles of glia (microglia and astrocytes) in: (a) creating and maintaining enhanced pain states such as neuropathic pain, and (b) compromising the efficacy of morphine and other opioids for pain control. While glia have little-to-no role in pain under basal conditions, pain is amplified when glia become activated, inducing the release of proinflammatory products, especially proinflammatory cytokines. How glia are triggered to become activated is a key issue, and appears to involve a number of neuron-to-glia signals including neuronal chemokines, neurotransmitters, and substances released by damaged, dying and dead neurons. In addition, glia become increasingly activated in response to repeated administration of opioids. Products of activated glia increase neuronal excitability via numerous mechanisms, including direct receptor-mediated actions, upregulation of excitatory amino acid receptor function, downregulation of GABA receptor function, and so on. These downstream effects of glial activation amplify pain, suppress acute opioid analgesia, contribute to the apparent loss of opioid analgesia upon repeated opioid administration (tolerance), and contribute to the development of opioid dependence. The potential implications of such glial regulation of pain and opioid actions are vast, suggestive that targeting glia and their proinflammatory products may provide a novel and effective therapy for controlling clinical pain syndromes and increasing the clinical utility of analgesic drugs.http://www.elsevier.com/wps/find/journaldescription.cws_home/622800/description#descriptio