RESUMEN
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. © 2003 International Association for the Study of Pain.
Asunto(s)
Animales , Citocinas , /envenenamiento , Óxido Nítrico/envenenamientoRESUMEN
Previous research indicates that the serotonergic neurons of the caudal dorsal raphe nucleus (DRN) are activated to a greater degree by inescapable shock (IS) as compared to escapable shock (ES), causing a greater release of serotonin (5-HT) in the DRN and in target regions. This differential activation is necessary for the behavioral changes that occur after exposure to IS, but not to ES (i.e. learned helplessness/behavioral depression). Although the critical role of the DRN in learned helplessness is clear, the neural inputs to the caudal DRN which result in this selective activation are unknown. One structure that may be involved in the activation of the DRN and the induction of learned helplessness/behavioral depression is the habenular complex. In experiment 1, habenula lesions eliminated the differential rise in DRN extracellular 5-HT levels in response to IS and ES exposure by severely attenuating the rise in 5-HT for both groups. In experiment 2, sham operated and habenula lesioned rats were exposed to either ES, IS or no stress (home cage control; HCC). Twenty-four hours later, sham rats previously exposed to IS exhibited longer escape latencies as compared to both ES and HCC rats (i.e. learned helplessness). The habenular lesion eliminated the differences in escape latency between groups, thus eliminating the induction of learned helplessness/behavioral depression. These results suggest that the habenula is necessary for the differential activation of the DRN and the escape deficits produced by IS.
Asunto(s)
Conducta Animal/fisiología , Habénula/fisiopatología , Núcleos del Rafe/metabolismo , Serotonina/metabolismo , Estrés Fisiológico/fisiopatología , Estrés Fisiológico/psicología , Animales , Electrochoque , Reacción de Fuga , Desamparo Adquirido , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the basolateral amygdala were measured by in vivo microdialysis. Inescapable, but not escapable, shock increased extracellular 5-HT in the amygdala relative to restrained controls. Basal levels of 5-HT were elevated 24 h after inescapable shock, and previously inescapably shocked subjects exhibited an exaggerated 5-HT response to two brief footshocks. Levels of extracellular 5-HIAA did not follow any particular pattern and were not correlated with the changes in 5-HT.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Condicionamiento Operante/fisiología , Reacción de Fuga/fisiología , Serotonina/metabolismo , Estrés Fisiológico/metabolismo , Análisis de Varianza , Animales , Electrochoque , Ácido Hidroxiindolacético/metabolismo , Masculino , Microdiálisis , Ratas , Ratas Sprague-DawleyRESUMEN
The effects of escapable and yoked inescapable electric tailshocks on extracellular levels of serotonin (5-HT) in the ventral hippocampus and dorsal periaqueductal gray (dPAG) were measured by in vivo microdialysis. Inescapable, but not escapable shock increased extracellular 5-HT in the ventral hippocampus relative to restrained controls. Basal levels of 5-HT were elevated 24 h after inescapable shock, and previously inescapably shocked subjects exhibited an exaggerated 5-HT response to 2 brief footshocks. In contrast, escapable, but not inescapable shock, increased extracellular 5-HT in the dPAG, increased basal 5-HT in the dPAG 24 h later, and led to an enhanced 5-HT response to subsequent brief footshock.