RESUMEN
The role of neuroinflammatory cells in the establishment of neuropathic pain has been investigated in depth in the last few years. In particular, microglia have been shown to be key players in the induction of tactile allodynia, as they release proinflammatory molecules that, in turn, sensitize nociceptive neurons within the spinal cord. However, the role of peripheral immune cells such as macrophages, infiltrating monocytes, mast cells, and T-cells has been highlighted in the last few studies, even though the data are still conflicting and need to be clarified. Intriguingly, the central (microglia) and peripheral (T-cell)-adaptive immune cells that orchestrate maladaptive process-driven neuropathic pain seem to be involved in a gender-dependent manner. In this review, we highlight the role of the microglia and peripheral immune cells in chronic degenerative disease associated with neuro-immune-inflammatory processes.
Asunto(s)
Neuralgia/etiología , Neuralgia/metabolismo , Neuroinmunomodulación , Animales , Femenino , Humanos , Hiperalgesia/etiología , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Sistema Inmunológico/citología , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Masculino , Microglía/inmunología , Microglía/metabolismo , Neuralgia/fisiopatología , Factores Sexuales , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The metabotropic glutamate receptor 7 (mGluR7) negative allosteric modulator, 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), was locally microinjected into the ventrolateral periaqueductal gray (VL PAG) and the effect on pain responses in formalin and spare nerve injury (SNI) -induced neuropathic pain models was monitored in the rat. The activity of rostral ventromedial medulla (RVM) "pronociceptive" ON and "antinociceptive" OFF cells was also evaluated. Intra-VL PAG MMPIP blocked the first and second phase of nocifensive behaviour in the formalin pain model. MMPIP increased the tail flick latency and simultaneously increased the activity of the OFF cells while inhibiting that of ON cells in rats with SNI of the sciatic nerve. MMPIP failed to modify nociceptive responses and associated RVM ON and OFF cell activity in sham rats. An increase in mGluR7 gene, protein and staining, the latter being associated with vesicular glutamate transporter-positive profiles, has been found in the VL PAG in SNI rats. Blockade of mGluR7 within the VL PAG has an antinociceptive effect in formalin and neuropathic pain models. VL PAG mGluR7 blockade offers a target for dis-inhibiting the VL PAG-RVM pathway and silencing pain in inflammatory and neuropathic pain models.
Asunto(s)
Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/metabolismo , Sustancia Gris Periacueductal/efectos de los fármacos , Sustancia Gris Periacueductal/metabolismo , Piridonas/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Masculino , Neuralgia/tratamiento farmacológico , Neuralgia/metabolismo , Piridonas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Human osteoclasts express functional TRPV1 channels, CB1/CB2 cannabinoid receptors and endocannabinoid/endovanilloid synthetic/catabolic enzymes. Pharmacologic manipulation of this system can modulate osteoclast activity. Here, through multidisciplinary approaches, we demonstrate that enzymes and receptors of the endocannabinoid/endovanilloid system are differently expressed in osteoclasts from menopausal women without or with osteoporosis. We report that in osteoclasts from osteoporotic patients, TRPV1 channels are upregulated and, if persistently stimulated with resiniferatoxin, become clustered to the plasma membrane while inducing a massive over-expression of CB2 receptors. By providing new evidence for a critical functional cross-talk between CB2 and TRPV1 receptors in osteoporosis, we speculate that TRPV1 desensitization, or its enhanced trafficking, together with TRPV1 agonist-induced CB2 receptor overexpression, might be critical to minimize calcium entry in osteoclasts, which could be in turn responsible of cell over-activation and higher bone resorption. Our data pave the way to the use of TRPV1 agonist together with CB2 agonists or CB1 antagonists in osteoporosis.
Asunto(s)
Moduladores de Receptores de Cannabinoides/metabolismo , Endocannabinoides , Osteoporosis/terapia , Canales Catiónicos TRPV/metabolismo , Fosfatasa Ácida/metabolismo , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Huesos/metabolismo , Calcio/metabolismo , Recuento de Células , Células Cultivadas , Femenino , Regulación de la Expresión Génica , Silenciador del Gen , Humanos , Inmunohistoquímica , Espacio Intracelular/metabolismo , Isoenzimas/metabolismo , Ligandos , Lipasa/genética , Lipasa/metabolismo , FN-kappa B/metabolismo , Osteoclastos/enzimología , Osteoclastos/patología , Osteoporosis/patología , Fosfolipasa D/genética , Fosfolipasa D/metabolismo , Polimorfismo de Nucleótido Simple/genética , Posmenopausia/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/genética , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/antagonistas & inhibidores , Receptor Cannabinoide CB2/genética , Receptor Cannabinoide CB2/metabolismo , Canales Catiónicos TRPV/genética , Fosfatasa Ácida TartratorresistenteRESUMEN
In this study we have investigated the role of periaqueductal grey prostaglandin receptors in formalin-induced hyperalgesia in mice. Glutamate and GABA release changes have been monitored by in vivo microdialysis. Intra-periaqueductal grey microinjections of misoprostol, a non-selective prostaglandin receptor agonist, increased nociceptive responses in the formalin test only during the late phase. Prostanoid EP(1) (L-335677), EP(2) (AH 6809), EP(3) (L-826266) and EP(4) (L-161982) receptor antagonists prevented the nociceptive response induced by misoprostol in formalin-injected mice. Prostanoid EP(1), EP(2), EP(3) and EP(4) antagonists reduced, per se, the late hyperalgesic phase. Intra-periaqueductal grey perfusion with misoprostol increased periaqueductal grey glutamate, whereas it produced an increase followed by a decrease in GABA. Likewise, formalin increased glutamate and produced a biphasic response on GABA. When misoprostol was perfused in combination with the peripheral injection of formalin, we observed an increase of glutamate and an increase followed by a stronger decrease in GABA release. These data show that periaqueductal grey prostaglandin receptor stimulation increased formalin-induced nociceptive response in the late phase by increasing glutamate release and by producing a biphasic change in GABA release.
Asunto(s)
Hiperalgesia/fisiopatología , Sustancia Gris Periacueductal/efectos de los fármacos , Receptores de Prostaglandina E/fisiología , Acetatos/farmacología , Acrilamidas/farmacología , Animales , Compuestos de Bencilo/farmacología , Dimetilsulfóxido/administración & dosificación , Dimetilsulfóxido/toxicidad , Líquido Extracelular/efectos de los fármacos , Líquido Extracelular/metabolismo , Formaldehído , Ácido Glutámico/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Inyecciones Intraventriculares , Masculino , Ratones , Microdiálisis , Misoprostol/administración & dosificación , Misoprostol/toxicidad , Naftalenos/farmacología , Dimensión del Dolor/métodos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/fisiopatología , Antagonistas de Prostaglandina/farmacología , Receptores de Prostaglandina E/antagonistas & inhibidores , Tiofenos/farmacología , Triazoles/farmacología , Xantonas/farmacología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
The aim of this study was to investigate the neurotransmissions involved in the antinociceptive effect of tramadol in the formalin test, which is an animal model of acute and tonic pain. A subcutaneous injection of formalin produces a biphasic nociceptive response: phase 1 (0-10 min-acute pain) and phase 2 (21-60 min-tonic pain). Nociceptive activity is reduced greatly during the 10 min between these two phases. We measured in mice the effects of (+/-)-tramadol, and of (+)- and (-)-tramadol administered before the induction of pain by formalin, in the presence and absence of drugs that act on the opioidergic, serotonergic and noradrenergic systems (naloxone, ketanserin, fluoxetine, maprotiline). With respect to animals treated with formalin alone, (+/-)-tramadol and its enantiomers significantly reduced the duration of nociceptive behaviours (lifting, licking, favouring, shaking, and flinching of the formalin-treated paw) during phase 2. This effect was prevented by the 5-HT(2) receptor antagonist ketanserin, but not by naloxone which, on the contrary, was able to prevent the antinociceptive effect of morphine. Naloxone and ketanserin did not affect the duration of nociceptive behaviour in animals not treated with tramadol. Fluoxetine (a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor), but not maprotiline (a selective norepinephrine reuptake inhibitor), potentiated the antinociceptive effect of (+/-)-tramadol. In conclusion, we demonstrate that the serotonergic pathway is responsible for the antinociceptive effect of tramadol in phase 2 of the formalin test, and that this effect is mediated by 5-HT(2) receptors.