RESUMEN
We have recently demonstrated a role of the vascular endothelium in peripheral pain mechanism by disrupting endothelial cell function using intravascular administration of octoxynol-9, a non-selective membrane active agent. As an independent test of the role of endothelial cells in pain mechanisms, we evaluated the effect of homocysteine, an agent that damages endothelial cell function. Mechanical stimulus-induced enhancement of endothelin-1 hyperalgesia in the gastrocnemius muscle of the rat was first prevented then enhanced by intravenous administration of homocysteine, but was only inhibited by its precursor, methionine. Both homocysteine and methionine significantly attenuated mechanical hyperalgesia in two models of ergonomic muscle pain, induced by exposure to vibration, and by eccentric exercise, and cutaneous mechanical hyperalgesia in an ischemia-reperfusion injury model of Complex Regional Pain Syndrome type I, all previously shown responsive to octoxynol-9. This study provides independent support for a role of the endothelial cell in pain syndromes thought to have a vascular basis, and suggests that substances that are endothelial cell toxins can enhance vascular pain.
Asunto(s)
Analgésicos no Narcóticos/farmacología , Fármacos Cardiovasculares/farmacología , Endotelio Vascular/efectos de los fármacos , Homocisteína/farmacología , Hiperalgesia/tratamiento farmacológico , Mialgia/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Endotelina-1 , Endotelio Vascular/fisiopatología , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Hipoxia-Isquemia Encefálica , Masculino , Metionina/farmacología , Movimiento , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiopatología , Mialgia/inducido químicamente , Mialgia/fisiopatología , Ratas Sprague-Dawley , Distrofia Simpática Refleja/tratamiento farmacológico , Distrofia Simpática Refleja/fisiopatología , Tacto , VibraciónRESUMEN
While blood vessels have long been implicated in diverse pain syndromes (e.g., migraine headache, angina pectoris, vasculitis, and Raynaud's syndrome), underlying mechanisms remain to be elucidated. Recent evidence supports a contribution of the vascular endothelium in endothelin-1-induced hyperalgesia, and its enhancement by repeated mechanical stimulation; a phenomenon referred to as stimulus-induced enhancement of (endothelin) hyperalgesia (SIEH). SIEH is thought to be mediated by release of ATP from endothelial cells, to act on P2X3 receptors on nociceptors. In the present study we evaluated the ability of another vasoactive hyperalgesic agent, epinephrine, to induce endothelial cell-dependent hyperalgesia and SIEH. We found that epinephrine also produces hyperalgesia and SIEH. Both P2X3 receptor antagonists, A317491 and octoxynol-9, which attenuate endothelial cell function, eliminated SIEH without affecting epinephrine hyperalgesia. We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache, whose receptors are present in endothelial cells - the triptans and ß blockers - have a vascular component to their anti-hyperalgesic action. For this, we tested the effect of ICI-118,551, a ß2-adrenergic receptor antagonist and sumatriptan, an agonist at 5-HT1B and 5-HT1D receptors, on nociceptive effects of endothelin and epinephrine. ICI-118,551 inhibited endothelin SIEH, and attenuated epinephrine hyperalgesia and SIEH. Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH, while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct-acting inflammatory mediator, prostaglandin E2. These results support the suggestion that triptans and ß-blockers interact with the endothelial cell component of the blood vessel to produce anti-hyperalgesia.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Células Endoteliales/efectos de los fármacos , Endotelina-1/farmacología , Epinefrina/farmacología , Hiperalgesia/inducido químicamente , Antagonistas Adrenérgicos beta/farmacología , Animales , Células Endoteliales/fisiología , Endotelinas/metabolismo , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Masculino , Octoxinol/farmacología , Fenoles/farmacología , Compuestos Policíclicos/farmacología , Propanolaminas/farmacología , Antagonistas del Receptor Purinérgico P2X/metabolismo , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1B/metabolismo , Receptor de Serotonina 5-HT1D/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Sumatriptán/farmacología , Triptaminas/farmacologíaRESUMEN
When comparing a cumulative dose-response curve for endothelin-1 (ET-1)-induced mechanical hyperalgesia to the effect of individual doses (1 ng, 10 ng, 100 ng, and 1 µg) administered in separate groups of rats, a marked difference was observed in the peak magnitude of hyperalgesia. Hyperalgesia was measured as decrease in the threshold for mechanically-induced withdrawal of the hind paw. The cumulative dosing protocol produced markedly greater maximum hyperalgesia. To determine whether this was due to the cumulative dosing protocol or to the repeated exposure to the mechanical test stimulus, we evaluated the impact of repeated testing on ET-1-induced mechanical hyperalgesia. While ET-1-induced mechanical hyperalgesia was dose- and time-dependent, repeated testing of nociceptive threshold, at 5 min intervals, following a single dose of ET-1, produced further decrease in nociceptive threshold. This mechanical stimulation-induced enhancement of ET-1 hyperalgesia lasted only 3-4 h, while the hyperalgesia lasted in excess of 5 days. The stimulation-enhanced hyperalgesia also occurred after a second injection of ET-1, administered 24 h after the initial dose. That this phenomenon is unique to ET-1 is suggested by the observation that while five additional, direct-acting hyperalgesic agents-prostaglandin E2 (PGE2), nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNFα)-induced robust mechanical hyperalgesia, none produced mechanical stimulation-enhanced hyperalgesia.
Asunto(s)
Endotelina-1/farmacología , Hiperalgesia/inducido químicamente , Estimulación Física/métodos , Animales , Dinoprostona/farmacología , Relación Dosis-Respuesta a Droga , Endotelina-1/administración & dosificación , Interleucina-6/farmacología , Masculino , Factores de Crecimiento Nervioso/farmacología , Umbral del Dolor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Taquifilaxis , Factores de Tiempo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.
Asunto(s)
Hiperalgesia/patología , Nociceptores/metabolismo , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacología , Analgésicos Opioides/uso terapéutico , Animales , Toxina del Cólera/metabolismo , Cisteína/efectos adversos , Cisteína/análogos & derivados , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Encefalina Ala(2)-MeFe(4)-Gli(5)/uso terapéutico , Factor Neurotrófico Derivado de la Línea Celular Glial/efectos adversos , Peroxidasa de Rábano Silvestre/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Masculino , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , S-Nitrosotioles/efectos adversos , Vasodilatadores/efectos adversosRESUMEN
We have previously described a rat model for the contribution of neuroplastic changes in nociceptors to the transition from acute to chronic pain. In this model a prior injury activates protein kinase C epsilon (PKCepsilon), inducing a chronic state characterized by marked prolongation of the hyperalgesia induced by inflammatory cytokines, prototypically prostaglandin E(2) (PGE(2)), referred to as hyperalgesic priming. In this study we evaluated the population of nociceptors involved in priming, by lesioning isolectin B4-positive (IB4(+)) nociceptors with intrathecal administration of a selective neurotoxin, IB4-saporin. To confirm that the remaining, TrkA(+)/IB4(-), nociceptors are still functional, we evaluated if nerve growth factor (NGF) induced hyperalgesia. While pretreatment with IB4-saporin eliminated the acute mechanical hyperalgesia induced by glia-derived neurotrophic factor (GDNF), NGF and PsiepsilonRACK, a highly selective activator of PKCepsilon, induced robust hyperalgesia. After injection of NGF, GDNF or PsiepsilonRACK, at a time at which hyperalgesia induced by PGE(2) is markedly prolonged (hyperalgesic priming) in control rats, in IB4-saporin-pretreated rats PGE(2) failed to produce this prolonged hyperalgesia. Thus, while PKCepsilon is present in most dorsal root ganglion neurons, where it can contribute to acute mechanical hyperalgesia, priming is restricted to IB4(+)-nociceptors, including those that are TrkA(+). While PKCepsilon activation can induce acute hyperalgesia in the IB4(+) population, it fails to induce priming. We suggest that hyperalgesic priming occurs only in IB4(+) nociceptors, and that in the peripheral terminals of nociceptors separate intracellular pools of PKCepsilon mediate nociceptor sensitization and the induction of hyperalgesic priming.
Asunto(s)
Glicoproteínas/análisis , Hiperalgesia/patología , Lectinas/análisis , Nociceptores/fisiología , Lectinas de Plantas/metabolismo , Animales , Dinoprostona/toxicidad , Activación Enzimática/efectos de los fármacos , Ganglios Espinales/patología , Factor Neurotrófico Derivado de la Línea Celular Glial/fisiología , Glicoproteínas/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Inyecciones Espinales , Lectinas/administración & dosificación , Lectinas/metabolismo , Lectinas/toxicidad , Masculino , Terminaciones Nerviosas/fisiología , Factor de Crecimiento Nervioso/toxicidad , Neuronas/efectos de los fármacos , Neurotoxinas/administración & dosificación , Neurotoxinas/toxicidad , Nociceptores/química , Nociceptores/efectos de los fármacos , Oligopéptidos/toxicidad , Proteína Quinasa C-epsilon/fisiología , Ratas , Ratas Sprague-Dawley , Receptor trkA/fisiología , Proteínas Inactivadoras de Ribosomas Tipo 1/administración & dosificación , Proteínas Inactivadoras de Ribosomas Tipo 1/toxicidad , Saporinas , Estrés Mecánico , VersicanosRESUMEN
The contribution of second messenger signaling, glucose level and sex hormones to sexual dimorphism in the streptozotocin model of diabetic painful peripheral neuropathy was evaluated. Streptozotocin induced elevation of blood glucose and mechanical hyperalgesia (measured by the Randall-Selitto paw-withdrawal test) were both greater in female rats. Ovariectomy abolished and estrogen implants reconstituted this sexual dimorphism; gonadectomy in males had no effect. An inhibitor of protein kinase Cepsilon attenuated hyperalgesia in males and ovariectomized females, but not in normal females or in ovariectomized females with estrogen implants, whereas inhibitors of protein kinase Cdelta attenuated hyperalgesia in females but not in males. Inhibitors of protein kinase A, protein kinase C (non-selective), protein kinase G and nitric oxide synthase attenuated hyperalgesia equally in both sexes. Higher blood glucose levels in diabetic females were also sex hormone dependent, and magnitude of hyperalgesia correlated with blood glucose level in diabetic male and female rats. These results demonstrate sexual dimorphism in diabetic hyperalgesia, mediated by sex hormone dependent differences in protein kinase Cepsilon and protein kinase Cdelta signaling and blood glucose levels and suggest that sex may be an important factor to be considered in the treatment of symptomatic diabetic neuropathy.
Asunto(s)
Diabetes Mellitus Experimental/enzimología , Isoformas de Proteínas/metabolismo , Proteína Quinasa C/metabolismo , Caracteres Sexuales , Animales , Antibacterianos , Glucemia/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Castración/métodos , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/inducido químicamente , Neuropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Estrógenos/administración & dosificación , Femenino , Gónadas/cirugía , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Masculino , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Ratas , EstreptozocinaRESUMEN
Painful peripheral neuropathy is a major dose-limiting adverse effect of many cancer chemotherapeutic agents, such as the vinca alkaloids and taxanes. Recent studies demonstrate sexual dimorphism in second-messenger signaling for primary afferent nociceptor sensitization, and a role of second messengers in the models of metabolic and toxic painful peripheral neuropathies. This study tested the hypothesis that sexual dimorphism alters the severity and second-messenger signaling pathways for enhanced nociception in an animal model of vincristine-induced painful peripheral neuropathy.I.V. injection of vincristine induced mechanical hyperalgesia that was greater in female rats. Gonadectomy in the females but not the males abolished the sex-dependent difference in mechanical hyperalgesia; this effect of gonadectomy in females was reversed by estrogen replacement. Inhibition of protein kinase C epsilon (PKC epsilon ) attenuated vincristine-induced hyperalgesia in males and ovariectomized females, but not in normal females or in estrogen-replaced ovariectomized females. Inhibitors of protein kinase A, protein kinase G, p42 / p44-mitogen activated protein kinase and nitric oxide synthase also attenuated vincristine-induced hyperalgesia, but to a similar degree in both sexes. These data demonstrate an estrogen-dependent sexual dimorphism in vincristine-induced hyperalgesia (female>male) and an unexpected opposite sexual dimorphism in the contribution of PKC epsilon to the severity of this hyperalgesia (male>female).