RESUMEN
Numerous reported data support the idea that Brain Derived Neurotrophic Factor (BDNF) is critically involved in both depression and comorbid pain. The possible direct effect of BDNF on pain mechanisms was assessed here and compared with behavioral/neurobiological features of neuropathic pain caused by chronic constriction injury to the sciatic nerve (CCI-SN). Sprague-Dawley male rats were either injected intrathecally with BDNF (3.0 ng i.t.) or subjected to unilateral CCI-SN. Their respective responses to anti-hyperalgesic drugs were assessed using the Randall-Selitto test and both immunohistochemical and RT-qPCR approaches were used to investigate molecular/cellular mechanisms underlying hyperalgesia in both models. Long lasting hyperalgesia and allodynia were induced by i.t. BDNF in intact healthy rats like those found after CCI-SN. Acute treatment with the BDNF-TrkB receptor antagonist cyclotraxin B completely prevented i.t. BDNF-induced hyperalgesia and partially reversed this symptom in both BDNF-pretreated and CCI-SN lesioned rats. Acute administration of the anticonvulsant pregabalin, the NMDA receptor antagonist ketamine, the opioid analgesics morphine and tapentadol or the antidepressant agomelatine also transiently reversed hyperalgesia in both i.t. BDNF injected- and CCI-SN lesioned-rats. Marked induction of microglia activation markers (OX42, Iba1, P-p38), proinflammatory cytokine IL-6, NMDA receptor subunit NR2B and BDNF was found in spinal cord and/or dorsal root ganglia of CCI-SN rats. A long lasting spinal BDNF overexpression was also observed in BDNF i.t. rats, indicating an autocrine self-induction, with downstream long lasting TrkB-mediated neuropathic-like pain. Accordingly, TrkB blockade appeared as a relevant approach to alleviate not only i.t. BDNF- but also nerve lesion-evoked neuropathic pain.
Asunto(s)
Analgésicos/farmacología , Modelos Animales de Enfermedad , Neuralgia/tratamiento farmacológico , Animales , Factor Neurotrófico Derivado del Encéfalo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/inmunología , Ganglios Espinales/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Inyecciones Espinales , Ligadura , Masculino , Neuralgia/patología , Neuralgia/fisiopatología , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Neuroglía/patología , Neuroinmunomodulación/efectos de los fármacos , Neuroinmunomodulación/fisiología , Ratas Sprague-Dawley , Nervio Ciático/lesiones , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/patología , TactoRESUMEN
Among monoamine neurotransmitters, serotonin (5-HT) is known to play complex modulatory roles in pain signaling mechanisms since the first reports, about forty years ago, on its essentially pro-nociceptive effects at the periphery and anti-nociceptive effects when injected directly at the spinal cord level. The discovery of multiple 5-HT receptor subtypes allowed possible explanations to this dual action at the periphery versus the central nervous system (CNS) since both excitatory and inhibitory effects can be exerted through 5-HT activation of different 5-HT receptors. However, it also appeared that activation of the same receptor subtype at CNS level might induce variable effects depending on the physiological or pathophysiological status of the animal administered with agonists. In particular, the marked neuroplastic changes induced by nerve lesion, which account for sensitization of pain signaling mechanisms, can contribute to dramatic changes in the effects of a given 5-HT receptor agonist in neuropathic rats versus intact healthy rats. This has notably been observed with 5-HT7 receptor agonists which exert a pronociceptive action in healthy rats but alleviate hyperalgesia consecutive to nerve lesion in neuropathic animals. Analysis of cellular mechanisms underlying such dual 5-HT actions mediated by a single receptor subtype indicates that the neuronal phenotype which expresses this receptor also plays a key role in determining which modulatory action 5-HT would finally exert on pain signaling mechanisms.
Asunto(s)
Dolor/metabolismo , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Animales , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Humanos , Dolor/patologíaRESUMEN
Previous studies showed that 5-hydroxytryptamine (5-HT)(1B/1D) receptor stimulation by triptans alleviates neuropathic pain caused by chronic constriction injury to the infraorbital nerve (CCI-ION) but not the sciatic nerve (CCI-SN) in rats. To assess whether such differential effects in the cephalic vs extracephalic territories is a property shared by other antimigraine drugs, we used the same models to investigate the effects of olcegepant, which has an antimigraine action mediated through calcitonin gene-related peptide (CGRP) receptor blockade. Adult male rats underwent unilateral CCI to the ION or the SN, and subsequent allodynia and/or hyperalgesia were assessed in ipsilateral vibrissal territory or hindpaw, respectively, using von Frey filaments and validated nociceptive tests. c-Fos expression was quantified by immunohistochemistry and interleukin 6 and activating transcription factor 3 (ATF3) mRNAs by real-time quantitative reverse transcriptase-polymerase chain reaction. Like naratriptan (0.1 to 0.3mg/kg, subcutaneously), olcegepant (0.3 to 0.9mg/kg, intravenously) markedly reduced mechanical allodynia in CCI-ION rats. In contrast, in CCI-SN rats, mechanical allodynia was completely unaffected and hyperalgesia was only marginally reduced by these drugs. A supra-additive antiallodynic effect was observed in CCI-ION rats treated with olcegepant (0.3mg/kg intravenously) plus naratriptan (0.1mg/kg subcutaneously), whereas this drug combination remained inactive in CCI-SN rats. Olcegepant (0.6mg/kg, intravenously) significantly reduced the number of c-Fos immunolabeled cells in spinal nucleus of the trigeminal nerve and upregulation of ATF3 transcript (a marker of neuron injury) but not that of interleukin-6 in trigeminal ganglion of CCI-ION rats. These findings suggest that CGRP receptor blockade might be of potential interest to alleviate trigeminal neuropathic pain.
Asunto(s)
Biomarcadores/metabolismo , Antagonistas del Receptor Peptídico Relacionado con el Gen de la Calcitonina , Dipéptidos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Quinazolinas/uso terapéutico , Factor de Transcripción Activador 3/efectos de los fármacos , Factor de Transcripción Activador 3/metabolismo , Animales , Interleucina-6/metabolismo , Locomoción/efectos de los fármacos , Masculino , Nervio Maxilar/lesiones , Nervio Maxilar/metabolismo , Neuralgia/etiología , Dimensión del Dolor , Piperazinas , Piperidinas/uso terapéutico , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Péptido Relacionado con el Gen de Calcitonina/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/uso terapéutico , Triptaminas/uso terapéuticoRESUMEN
Among receptors mediating serotonin actions in pain control, the 5-HT(7)R is of special interest because it is expressed by primary afferent fibers and intrinsic GABAergic and opioidergic interneurons within the spinal dorsal horn. Herein, we investigated whether GABA and/or opioids contribute to 5-HT(7)R-mediated control of neuropathic pain caused by nerve ligation. Acute administration of 5-HT(7)R agonists (AS-19, MSD-5a, E-55888) was found to markedly reduce mechanical and thermal hyperalgesia in rats with unilateral constriction injury to the sciatic nerve (CCI-SN). In contrast, mechanical hypersensitivity caused by unilateral constriction injury to the infraorbital nerve was essentially unaffected by these ligands. Further characterization of the anti-hyperalgesic effect of 5-HT(7)R activation by the selective agonist E-55888 showed that it was associated with a decrease in IL-1ß mRNA overexpression in ipsilateral L4-L6 dorsal root ganglia and lumbar dorsal horn in CCI-SN rats. In addition, E-55888 diminished CCI-SN-associated increase in c-Fos immunolabeling in superficial laminae of the lumbar dorsal horn and the locus coeruleus, but increased c-Fos immunolabeling in the nucleus tractus solitarius and the parabrachial area in both control and CCI-SN rats. When injected intrathecally (i.t.), bicuculline (3 µg i.t.), but neither phaclofen (5 µg i.t.) nor naloxone (10 µg i.t.), significantly reduced the anti-hyperalgesic effects of 5-HT(7)R activation (E-55888, 10 mg/kg s.c.) in CCI-SN rats. These data support the idea that 5-HT(7)R-mediated inhibitory control of neuropathic pain is underlain by excitation of GABAergic interneurons within the dorsal horn. In addition, 5-HT(7)R activation-induced c-Fos increase in the nucleus tractus solitarius and the parabrachial area suggests that supraspinal mechanisms might also be involved.
Asunto(s)
Analgésicos Opioides/farmacología , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Receptores de Serotonina/efectos de los fármacos , Ácido gamma-Aminobutírico/farmacología , Analgésicos Opioides/antagonistas & inhibidores , Animales , Inmersión/fisiopatología , Inmunohistoquímica , Interneuronas/efectos de los fármacos , Dimensión del Dolor/efectos de los fármacos , Estimulación Física , Presión , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Neuropatía Ciática/tratamiento farmacológico , Neuropatía Ciática/patología , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Temperatura Cutánea/efectos de los fármacosRESUMEN
Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain caused by such lesion. We herein investigated whether the blockade of TTX-sensitive channels could reduce pain-related behaviors and evoked c-Fos immunoreactivity in rats with neuropathic pain produced by chronic unilateral constriction injury to either the sciatic nerve or the infraorbital nerve. Acute as well as subchronic administration of TTX (1-6 mug/kg s.c.) was found to suppress for up to 3 h allodynia and hyperalgesia in sciatic nerve-ligated rats. In contrast, TTX was only moderately effective in rats with ligated infraorbital nerve. In sciatic nerve-ligated rats, TTX administration prevented the increased c-Fos immunoreactivity occurring in the dorsal horn of the lumbar cord and some supraspinal areas in response to light mechanical stimulation of the nerve-injured hindpaw. The anti-allodynia/antihyperalgesia caused by TTX in these neuropathic rats was promoted by combined treatment with naloxone (0.5 mg/kg s.c.) but unaffected by the 5-HT(1B) receptor antagonist F11648 (0.5 mg/kg s.c.) and the alpha(2)-adrenergic receptor antagonist idazoxan (0.5 mg/kg i.v.). In contrast, the anti-allodynic and anti-hyperalgesic effects of TTX were significantly attenuated by co-administration of morphine (3 mg/kg s.c.) or the cholecystokinin(2)-receptor antagonist CI-1015 (0.1 mg/kg i.p.). These results indicate that TTX alleviates pain-related behaviors in sciatic nerve-lesioned rats through mechanisms that involve complex interactions with opioidergic systems.
Asunto(s)
Anestésicos Locales/farmacología , Enfermedades de los Nervios Craneales/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Neuropatía Ciática/tratamiento farmacológico , Tetrodotoxina/farmacología , Anestésicos Locales/administración & dosificación , Animales , Enfermedad Crónica , Enfermedades de los Nervios Craneales/metabolismo , Quimioterapia Combinada , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Inmunohistoquímica , Vértebras Lumbares , Masculino , Neuralgia/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Neuropatía Ciática/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Tetrodotoxina/administración & dosificación , Factores de TiempoRESUMEN
A study of 257 French invasive pneumococci isolated between 2000 and 2002 showed high rates of nonsusceptibility to penicillin and macrolides (50%), contrasting with a low frequency of resistance to amoxicillin or levofloxacin (<1%) and tolerance to vancomycin (0%). The genetic homogeneity of some serogroups, including serogroup 1, enhanced the risk of epidemiological changes.