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1.
Blood Cells Mol Dis ; 54(2): 155-9, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25486928

RESUMEN

Children with sickle cell disease (SCD) have painful vaso-occlusive episodes (VOEs), which often reoccur across the individual's lifespan. Vaso-constrictive and vaso-dilatory molecules have been hypothesized to play a role in VOEs. Endothelin-1 (ET-1) is a potent vasoconstrictor that is released during VOEs and is correlated with pain history. Apelin is a vaso-dilatory peptide that also has a modulatory role in pain processing. We hypothesize that the ratio between vaso-dilatory and vaso-constrictive tone in children with SCD may be a marker of pain sensitization and vaso-occlusion. Plasma endothelin and apelin levels were measured in 47 children with SCD. Procedural pain and baseline pain were assessed via child- and caregiver-reports and observational distress. Pain history was assessed using retrospective chart review. Plasma apelin was related to age, with decreased levels in older children. The ratio between apelin and ET-1 was negatively correlated to observational baseline pain. The ratio between apelin and Big ET was negatively correlated to caregiver ratings of baseline pain and positively correlated to history of VOEs, which is possibly due to hydroxyurea treatment. These results suggest that an imbalance in the apelin and endothelin systems may contribute to an increasing number of VOEs and baseline pain in children with SCD.


Asunto(s)
Anemia de Células Falciformes/genética , Endotelina-1/genética , Péptidos y Proteínas de Señalización Intercelular/genética , Dolor/genética , Vasoconstricción , Vasodilatación , Adolescente , Factores de Edad , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Anemia de Células Falciformes/fisiopatología , Antidrepanocíticos/uso terapéutico , Apelina , Biomarcadores/sangre , Niño , Preescolar , Endotelina-1/sangre , Femenino , Regulación de la Expresión Génica , Humanos , Hidroxiurea/uso terapéutico , Péptidos y Proteínas de Señalización Intercelular/sangre , Masculino , Dolor/sangre , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Dimensión del Dolor , Transducción de Señal
2.
Int J Pharm Compd ; 28(2): 100-109, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38604146

RESUMEN

Pain syndromes are among the most widespread, costly, and debilitating of all neurological disorders. The number of patients living with chronic pain is expected to increase with the aging population and with the rise in obesity and diabetes across the nation. This type of pain is often insensitive to the traditional pain pharmacopeia or surgical intervention. Over the last 10 years the number of prescriptions that have been compounded by pharmacists has increased dramatically. There are a number of drugs in the area of pain management that have been formulated and compounded by pharmacists to treat conditions such as diabetic neuropathy, fibromyalgia, postherpetic neuralgia, joint pain, arthritis, and a variety of other conditions. A significant portion of these compounded analgesic preparations is made up of topical/transdermal dosage forms such as gels and creams. While the efficacy and doses of these drugs in systemic dosage forms have been widely established, little is known about the permeation and efficacy of these compounds from topical/transdermal gels. This review will provide an overview of chronic pain as a disease, the mechanisms of chronic pain, current treatment approaches to chronic pain, and a discussion of the drugs that are typically compounded into these topical formulations and studied in clinical trials.


Asunto(s)
Dolor Crónico , Neuralgia Posherpética , Neuralgia , Humanos , Analgésicos , Dolor Crónico/tratamiento farmacológico , Geles/uso terapéutico , Neuralgia/tratamiento farmacológico , Neuralgia Posherpética/tratamiento farmacológico
3.
Pain Manag Nurs ; 14(3): e54-8, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23972871

RESUMEN

This study examined the frequency of information-seeking coping behaviors in 37 African-American children (ages 5-17 years) with sickle cell disease during venipuncture. The relationships between coping behaviors and child- and parent-reported pain and observational distress were also assessed. The majority of children attended to the procedure, but did not seek information via questions. This pattern of coping was only partially effective at reducing distress and had no relation to pain. This pattern of coping is discussed within the context of cultural factors that may be important in understanding responses to procedural pain in pediatric sickle cell disease.


Asunto(s)
Dolor Agudo/enfermería , Dolor Agudo/psicología , Adaptación Psicológica , Anemia de Células Falciformes/enfermería , Anemia de Células Falciformes/psicología , Negro o Afroamericano/psicología , Adolescente , Niño , Femenino , Educación en Salud , Humanos , Masculino , Padres/psicología , Enfermería Pediátrica/métodos , Flebotomía/efectos adversos , Flebotomía/enfermería , Flebotomía/psicología , Autoinforme
4.
J Undergrad Neurosci Educ ; 9(2): A84-91, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-23494013

RESUMEN

The journal IMPULSE offers undergraduates worldwide the opportunity to publish research and serve as peer reviewers for the submissions of others. Undergraduate faculty have recognized the journal's value in engaging students working in their labs in the publication process. However, integration of scientific publication into an undergraduate laboratory classroom setting has been lacking. We report here on a course at Ursinus College where 20 students taking Molecular Neurobiology were required to submit manuscripts to IMPULSE. The syllabus allowed for the laboratory research to coincide with the background research and writing of the manuscript. Students completed their projects on the impact of drugs on the Daphnia magna nervous system while producing manuscripts ready for submission by week 7 of the course. Findings from a survey completed by the students and perceptions of the faculty member teaching the course indicated that students spent much more time writing, were more focused on completing the assays, completed the assays with larger data sets, were more engaged in learning the scientific concepts and were more thorough with their revisions of the paper knowing that it might be published. Further, the professor found she was more thorough in critiquing students' papers knowing they would be externally reviewed. Incorporating journal submission into the course stimulated an in depth writing experience and allowed for a deeper exploration of the topic than students would have experienced otherwise. This case study provides evidence that IMPULSE can be successfully used as a means of incorporating scientific publication into an undergraduate laboratory science course. This approach to teaching undergraduate neuroscience allows for a larger number of students to have hands-on research and scientific publishing experience than would be possible with the current model of a few students in a faculty member's laboratory. This report illustrates that IMPULSE can be incorporated as an integral part of an academic curriculum with positive outcomes on student engagement and performance.

5.
Neurosci Lett ; 451(1): 89-93, 2009 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-19111903

RESUMEN

Endothelin (ET)-1 is a chemical mediator released by the body at sites of injury and disease and is involved in various painful states. This study examined whether ET-1 exposure in the neonatal period alters subsequent ET-1 induced nociception and expression of the ET(B) receptor. ET-1 or saline was administered to postnatal day 7 rats. On postnatal day 11, ET-1 or saline was administered; a first exposure to ET-1 for one group, and a second exposure to ET-1 for another group. A statistically significant increase in ET-1 induced paw flinching was observed in postnatal day 11 male rats exposed to ET-1 for the second time as compared to male rats exposed to ET-1 for the first time. In contrast, a statistically significant decrease in ET-1 induced paw flinching was observed in postnatal day 11 female rats exposed to ET-1 for the second time as compared to female rats exposed to ET-1 for the first time. Furthermore, in males a positive correlation was found between ET-1 induced paw flinching on postnatal day 7 versus 11. In contrast, in females a negative correlation was found between ET-1 induced paw flinching on postnatal day 7 versus 11. Changes in behavioral sensitivity to ET-1 were accompanied by sex-specific ET-1 induced changes in expression of the ET(B) receptor on postnatal day 11 in the plantar hind paw with a statistically significant decrease and increase in ET(B) receptor expression in males and females, respectively. These findings suggest that ET-1 exposure in the neonatal period sex-specifically alters expression of the ET(B) receptor and behavioral sensitivity to ET-1 whereby males show sensitization and females show de-sensitization.


Asunto(s)
Envejecimiento/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Endotelina-1/farmacología , Umbral del Dolor/efectos de los fármacos , Receptor de Endotelina B/efectos de los fármacos , Envejecimiento/metabolismo , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Encéfalo/metabolismo , Tolerancia a Medicamentos/fisiología , Endotelina-1/metabolismo , Femenino , Masculino , Dolor/inducido químicamente , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor , Umbral del Dolor/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptor de Endotelina B/metabolismo , Caracteres Sexuales
6.
Anesthesiology ; 108(2): 305-13, 2008 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-18212576

RESUMEN

BACKGROUND: The use of opioids to treat pain is often limited by side effects mediated through the central nervous system. The current study used a recombinant herpes simplex virus type 1 to increase expression of the mu-opioid receptor (muOR) in primary afferent neurons. The goal of this strategy was to enhance peripheral opioid analgesia. METHODS: Cutaneous inoculation with herpes simplex virus containing muOR complementary DNA (cDNA) in antisense (SGAMOR) or sense (SGMOR) orientation relative to a constitutive promoter, or complementary DNA for Escherichia coli lac Z gene as a control virus (SGZ) was used to modify the levels of muOR in primary afferents. The effects of altered muOR levels on peripheral analgesia were then examined. RESULTS: At 4 weeks after SGAMOR and SGMOR infection, decreased and increased muOR immunoreactivity was observed in ipsilateral dorsal hind paw skin, lumbar dorsal root ganglion cells, and superficial dorsal horns, respectively, compared with SGZ. This change in muOR expression in mice by SGAMOR and SGMOR was accompanied at the behavioral level with a rightward and leftward shift in the loperamide dose-response curve, respectively, compared with SGZ. CONCLUSIONS: This gene therapy approach may provide an innovative strategy to enhance peripheral opioid analgesia for the treatment of pain in humans, thereby minimizing centrally mediated opioid side effects such as sedation and addiction.


Asunto(s)
Analgesia/métodos , Loperamida/farmacología , Receptores Opioides mu/genética , Anestesia Raquidea , Animales , ADN Complementario/genética , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiología , Técnicas de Transferencia de Gen , Herpesviridae/genética , Ratones , Terminaciones Nerviosas/efectos de los fármacos , Terminaciones Nerviosas/fisiología , Piel/inervación , Médula Espinal/efectos de los fármacos , Médula Espinal/fisiología
7.
Brain Res ; 1199: 82-90, 2008 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-18267316

RESUMEN

The recognition of the impact of neonatal pain experience on subsequent sensory processing has led to the increased advocacy for the use of opioids for pain relief in infants. However, following long-term opioid exposure in intensive care units more than 48% of infants exhibited behaviors indicative of opioid abstinence syndrome, a developmentally equivalent set of behaviors to opioid withdrawal as seen in adults. Little is known about the long-term influence of repeated neonatal morphine exposure on nociception and analgesia. To investigate this, we examined mechanical and thermal nociception on postnatal days 11, 13, 15, 19, 24, 29, 39 and 48 following subcutaneous administration of morphine (3 mg/kg) once daily on postnatal days 1-9. The cumulative morphine dose-response was assessed on postnatal days 20 and 49, and stress-induced analgesia was assessed on postnatal days 29 and 49. Both basal mechanical and thermal nociception in neonatal, morphine-exposed rats were significantly lower than those in saline-exposed, handled-control rats and naive rats until P29. A rightward-shift of cumulative dose-response curves for morphine analgesia upon chronic neonatal morphine was observed both on P20 and P49. The swim stress-induced analgesia was significantly decreased in neonatal morphine-exposed rats on P29, but not on P49. These data indicate that morphine exposure equivalent to the third trimester of gestation produced prolonged pain hypersensitivity, decreased morphine antinociception, and decreased stress-induced analgesia. The present study illustrates the need to examine the long-term influence of prenatal morphine exposure on pain and analgesia in the human pediatric population.


Asunto(s)
Analgesia , Analgésicos Opioides/administración & dosificación , Morfina/administración & dosificación , Umbral del Dolor/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Tolerancia a Medicamentos , Femenino , Hiperalgesia/fisiopatología , Masculino , Dimensión del Dolor/métodos , Embarazo , Ratas , Tiempo de Reacción/efectos de los fármacos
8.
J Pain ; 8(8): 657-66, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17553749

RESUMEN

UNLABELLED: Endothelin-1 (ET-1) is a chemical mediator released by the body at sites of injury and disease. This study tests the hypothesis that ET-1-induced nociception changes with age and sex. Intraplantar ET-1 (1.1 and 3.3 nmol) produced age-specific paw flinching and licking (postnatal day 7 > 21 > 60). The onset and duration of the nociceptive responses was dependent on age. Postnatal day (P) 21 and 60 rats displayed an immediate onset of behavior that subsided with time, whereas the P7 rats had a delayed behavioral response that onset at 20 minutes after ET-1 administration and continued beyond the 75 minute observation period. P7 males showed greater paw flinching compared with females. In addition to spontaneous nociceptive behaviors, ET-1 produced mechanical allodynia in all ages. As with spontaneous nociception, ET-1-induced mechanical allodynia was of a longer duration in the younger aged rats compared with adult rats. These findings show that ET-1 produces both spontaneous nociceptive behaviors and evoked mechanical allodynia in both young and adult rats but that the temporal profile and the size of the responses are age- and sex-dependent. These findings are the first description of age- and sex-specific ET-1-induced nociception. PERSPECTIVE: Endothelin-1 is a vasoactive peptide released into the systemic circulation after stress and cold pain as well as locally in tissue after injury and disease. These findings suggest greater pain to stimuli that release endogenous endothelin in younger versus older organisms. This developmental approach to studying ET-1-induced pain further illustrates the need for understanding pain mechanisms as a function of the development of the organism so as to better treat pain across the life span.


Asunto(s)
Envejecimiento/fisiología , Endotelina-1 , Dolor/inducido químicamente , Dolor/fisiopatología , Caracteres Sexuales , Análisis de Varianza , Animales , Animales Recién Nacidos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Umbral Sensorial/efectos de los fármacos , Factores de Tiempo
9.
Neurosci Lett ; 400(1-2): 154-7, 2006 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-16517072

RESUMEN

The present study tested the hypothesis that morphine exposure during the human developmental equivalent of the third trimester would alter inflammatory pain. This study examined whether acute or continuous opioid exposure in the neonatal rat alters formalin-induced nociception after 4 days of abstinence. Rats were exposed to a single acute administration of morphine on postnatal day 7 or 72 h of opioid infusion from postnatal days 5-7 via osmotic pump. When challenged with intraplantar formalin on postnatal day 11, rats exposed to acute or chronic morphine had increased phase II pain-associated behaviors. These findings suggest that neonatal morphine exposure may have unintended consequences on inflammatory pain.


Asunto(s)
Morfina/administración & dosificación , Dolor/tratamiento farmacológico , Animales , Animales Recién Nacidos , Conducta Animal , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Formaldehído , Masculino , Dolor/inducido químicamente , Dimensión del Dolor , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
10.
Diabetes Educ ; 32(2): 197-210, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-16554422

RESUMEN

With diabetes affecting 5% to 10% of the US population, development of a more effective treatment for chronic diabetic wounds is imperative. Clinically, the current treatment in topical wound management includes debridement, topical antibiotics, and a state-of-the-art topical dressing. State-of-the-art dressings are a multi-layer system that can include a collagen cellulose substrate, neonatal foreskin fibroblasts, growth factor containing cream, and a silicone sheet covering for moisture control. Wound healing time can be up to 20 weeks. The future of diabetic wound healing lies in the development of more effective artificial "smart" matrix skin substitutes. This review article will highlight the need for novel smart matrix therapies. These smart matrices will release a multitude of growth factors, cytokines, and bioactive peptide fragments in a temporally and spatially specific, event-driven manner. This timed and focal release of cytokines, enzymes, and pharmacological agents should promote optimal tissue regeneration and repair of full-thickness wounds. Development of these kinds of therapies will require multidisciplinary translational research teams. This review article outlines how current advances in proteomics and genomics can be incorporated into a multidisciplinary translational research approach for developing novel smart matrix dressings for ulcer treatment. With the recognition that the research approach will require both time and money, the best treatment approach is the prevention of diabetic ulcers through better foot care, education, and glycemic control.


Asunto(s)
Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus/fisiopatología , Cicatrización de Heridas , Heridas y Lesiones/terapia , Complicaciones de la Diabetes/terapia , Matriz Extracelular/fisiología , Humanos , Inflamación/fisiopatología , Inflamación/terapia , Neovascularización Fisiológica , Grupo de Atención al Paciente , Heridas y Lesiones/fisiopatología
11.
J Pain ; 6(8): 535-49, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16084468

RESUMEN

UNLABELLED: Ethanol (EtOH) withdrawal increases sensitivity to painful stimuli in adult rats. In this study, withdrawal from a single, acute administration of EtOH dose-dependently produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 (P7) rats. In contrast, P21 rats exhibited earlier and more prolonged mechanical allodynia but not thermal hyperalgesia. For both P7 and P21 rats, blood and spinal cord EtOH levels peaked at 30 minutes after administration, with P7 rats achieving overall higher spinal cord concentrations. Protein kinase C (PKC) has been implicated in mediating pain responses. Inhibitory PKC- and gamma-specific peptides attenuated mechanical allodynia and thermal hyperalgesia in P7 rats, whereas only the PKCgamma inhibitor prevented mechanical allodynia in P21 rats. Immunoreactive PKC in dorsal root ganglion and PKCgamma in lumbar spinal cord increased at 6 hours after EtOH administration in P7 rats. In P21 rats, the density of PKC immunoreactivity remained unchanged, whereas the density of PKCgamma immunoreactivity increased and translocation occurred. These studies demonstrate developmental differences in neonatal nociceptive responses after withdrawal from acute EtOH and implicate a role for specific PKC isozymes in EtOH withdrawal-associated allodynia and hyperalgesia. PERSPECTIVE: This study examines age-specific nociceptive responses after ethanol exposure by using 2 different ages of rats. The results suggest that ethanol age-dependently alters sensitivity to mechanical and thermal stimuli via specific protein kinase C isozymes. These results begin to ascertain the mechanisms that produce abnormal pain after alcohol exposure.


Asunto(s)
Trastornos del Sistema Nervioso Inducidos por Alcohol/enzimología , Etanol/efectos adversos , Hiperalgesia/enzimología , Proteína Quinasa C-epsilon/efectos de los fármacos , Proteína Quinasa C/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/enzimología , Factores de Edad , Envejecimiento/fisiología , Trastornos del Sistema Nervioso Inducidos por Alcohol/fisiopatología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/enzimología , Encéfalo/fisiopatología , Depresores del Sistema Nervioso Central/efectos adversos , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Femenino , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Inmunohistoquímica , Isoenzimas/efectos de los fármacos , Isoenzimas/metabolismo , Masculino , Péptidos/farmacología , Proteína Quinasa C/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Transporte de Proteínas/efectos de los fármacos , Transporte de Proteínas/fisiología , Ratas , Ratas Sprague-Dawley , Síndrome de Abstinencia a Sustancias/fisiopatología
12.
Eur J Pain ; 9(3): 233-42, 2005 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15862472

RESUMEN

The current study tested the hypothesis that repetitive activation of sciatic Adelta-afferents evokes a saphenous C-afferent hypoalgesia mediated by pre-synaptic GABA(B) receptors. Tonic activation of sciatic Adelta-afferents was produced by cutaneous application of dimethyl sulfoxide (DMSO) followed by repetitive thermal activation of Adelta-afferents on the dorsolateral hind paw. The tonic activation of sciatic Adelta-afferents produced hypoalgesia in saphenous C-afferents. Intrathecal administration of the GABA(B) receptor antagonist, saclofen, attenuated saphenous hypoalgesia demonstrating at least partial mediation by central GABA(B) receptors. To determine if this central GABA(B) receptor activation occurs at pre-synaptic primary afferent terminals or postsynaptic spinal cord neurons, the dorsal hind paws of mice were infected with a recombinant herpes simplex virus type 1 (HSV-1) designed to selectively knock down expression of the GABA(B1a) receptor subunit (PAGB1a) in primary afferents or a control virus encoding the E. coli lacZ gene (PZ). Four weeks after infection, GABA(B) receptor immunoreactivity in the superficial dorsal horns ipsilateral to PAGB1a application was reduced and hypoalgesia in saphenous C-afferents was attenuated when compared to PZ-infected mice. These findings indicate an intersegmental, sciatic Adelta-afferent-evoked hypoalgesic effect on saphenous C-afferent responses that is mediated by pre-synaptic GABA(B) receptors on the terminals of those C-afferents.


Asunto(s)
Hipoestesia/fisiopatología , Fibras Nerviosas Mielínicas/fisiología , Fibras Nerviosas Amielínicas/fisiología , Terminales Presinápticos/fisiología , Receptores de GABA-B/fisiología , Nervio Ciático/fisiopatología , Vías Aferentes/fisiopatología , Animales , Masculino , Ratones , Estimulación Física , Tiempo de Reacción/fisiología , Transmisión Sináptica/fisiología
13.
J Pain ; 16(3): 283-90, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25576797

RESUMEN

UNLABELLED: Chronic neuropathic pain is often difficult to treat with current pain medications. Gene therapy is presently being explored as a therapeutic approach for the treatment of neuropathic and cancer pain. In this study, we sought to use an injury-specific promoter to deliver the mu-opioid receptor (MOR) transgene such that expression would occur during the injured state only in response to release of injury-specific galanin. To determine whether an injury-specific promoter can produce neuron-specific MOR expression and enhanced antinociception, we compared animals infected with a galanin promoter virus (galMOR) or a human cytomegalovirus promoter virus (cmvMOR). In behavioral assays, we found an earlier onset and a larger magnitude of antinociception in animals infected with galMOR compared with cmvMOR. Immunohistochemical analysis of dorsal root ganglion neurons revealed a significant increase in MOR-positive staining in cmvMOR- and galMOR-treated mice. Spinal cord sections from galMOR-treated mice showed a greater increase in density but not area of MOR-positive staining. These results suggest that using injury-specific promoters to drive gene expression in primary afferent neurons can influence the onset and magnitude of antinociception in a rodent model of neuropathic pain and can be used to upregulate MOR expression in populations of neurons that are potentially injury specific. PERSPECTIVE: An injury-specific promoter (galMOR) was used to drive MOR expression in a population- and injury-specific manner. GalMOR increased antinociception and density of MOR staining in the spinal cord. This article presents evidence that promoter selection is an important component in successful gene expression in an injury- and population-specific manner.


Asunto(s)
Terapia Genética/métodos , Neuralgia/terapia , Regiones Promotoras Genéticas , Receptores Opioides mu/genética , Simplexvirus/genética , Animales , Citomegalovirus/genética , Modelos Animales de Enfermedad , Femenino , Galanina/genética , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Calor , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Hiperalgesia/terapia , Inmunohistoquímica , Vértebras Lumbares , Ratones , Neuralgia/patología , Neuralgia/fisiopatología , Neuronas Aferentes/patología , Neuronas Aferentes/fisiología , Receptores Opioides mu/metabolismo , Médula Espinal/patología , Médula Espinal/fisiopatología , Nervios Espinales/lesiones , Tacto
14.
Pain ; 100(1-2): 163-70, 2002 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-12435469

RESUMEN

The present study was undertaken to determine whether leukocytes are recruited into the spinal cord following a peripheral L5 spinal nerve transection that results in mechanical allodynia (increased tactile sensitivity behavior correlates with neuropathic pain). In rats subjected to bone marrow irradiation, donor-specific major histocompatibility complex (MHC) class I (I1-69) positive peripheral immune cells trafficked to the L5 spinal cord in response to an L5 spinal nerve injury. The number of I1-69 positive cell profiles increased over time and correlated with increased mechanical allodynia. At early time points following injury, I1-69 positive immune cells co-regionalized with the expression of the macrophage marker ED2. At later time points following injury, some of the infiltrating immune cells did not co-regionalize with the macrophage marker ED2. At no time did the infiltrating cells co-regionalize with the neuronal marker (NeuN). Both macrophage-like morphology and T cell-like morphology were observed in the I1-69 positive cellular infiltrate. Conversely, animals that underwent sham surgery demonstrated little mechanical allodynia and a minimal number of infiltrating peripheral immune cells. In a separate group of rats, infiltration of CD3+ T-lymphocytes was confirmed at 14 days post-nerve transection. This study demonstrates trafficking of leukocytes into the lumbar spinal cord at time points that correlate with mechanical allodynia suggesting a role of central neuroinflammation in persistent neuropathic pain.


Asunto(s)
Macrófagos/inmunología , Neuralgia/inmunología , Médula Espinal/inmunología , Nervios Espinales/lesiones , Linfocitos T/inmunología , Animales , Movimiento Celular/inmunología , Desnervación , Antígenos de Histocompatibilidad Clase I/inmunología , Masculino , Neuroinmunomodulación/inmunología , Quimera por Radiación , Radiculopatía/inmunología , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Médula Espinal/citología , Nervios Espinales/inmunología
15.
Pain ; 106(3): 365-371, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14659519

RESUMEN

Spinal application of opiates is the cornerstone of potent analgesia. In the present study, opiate analgesia was investigated after cutaneous application of a recombinant herpes simplex virus type-1 (HSV-1) encoding micro-opioid receptor (microOR) cDNA in reverse orientation with respect to the human cytomegalovirus early enhancer-promoter. Hind paw application of this recombinant vector was used in order to attenuate expression of the microOR in primary afferents and determine whether recombinant vector application would differentially affect the antinociceptive effects of the specific microOR agonist, [D-Ala(2),N-MePhe(4),Gly-ol(5)] enkephalin (DAMGO), on behavioral responses mediated by C- and Adelta-thermonociceptors. The recombinant vector encoding the Escherichia coli lacZ gene marker, KHZ, served as a control virus. Dorsal hind paw surfaces of female Swiss-Webster mice were treated with one of these two viruses (1x10(8)pfu, 10 microl) or vehicle (uninfected). Immunohistochemistry and quantitative image analyses revealed decreased microOR expression in the superficial dorsal horns ipsilateral to hind paws treated with AMOR, but not KHZ. To add, behavioral foot withdrawal latencies of AMOR- and KHZ-treated hind paws demonstrated dose-dependent antinociception after intrathecal DAMGO administration. However, cutaneous application of dorsal hind paw surfaces treated with AMOR, but not KHZ, caused a rightward shift in the C-fiber dose-response, thus, indicating a loss of potency of intrathecal DAMGO. Loss or diminution of DAMGO potency during Adelta-fiber-mediated responses was not observed. These immunohistochemistry and behavioral results of novel, recombinant HSV-1 vector microOR 'knock-down' in nociceptor afferent fibers provide additional evidence for presynaptic localization of microORs on central C-, but not Adelta-terminals.


Asunto(s)
Analgésicos Opioides/farmacología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Receptores Opioides mu/deficiencia , Animales , Relación Dosis-Respuesta a Droga , Encefalina Ala(2)-MeFe(4)-Gli(5)/farmacología , Femenino , Vectores Genéticos/genética , Vectores Genéticos/metabolismo , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/metabolismo , Masculino , Ratones , Receptores Opioides mu/agonistas , Receptores Opioides mu/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
16.
Pain ; 110(1-2): 269-80, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15275777

RESUMEN

Upon withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. We present evidence that neonatal rats exhibit allodynia and hyperalgesia on acute opiate withdrawal. Postnatal 7 and 21 day rats were used to approximately model a full term human infant and a human child, respectively. The opiate antagonist naloxone was used to precipitate withdrawal at 30 or 120 min after a single acute administration of morphine. Alternatively, rats were allowed to undergo spontaneous withdrawal. Behavioral manifestations of withdrawal syndrome were not observed when naloxone was administered at 30 min post-morphine, but were present when withdrawal was precipitated at 120 min. Spontaneous and precipitated withdrawal from a single acute administration of morphine produced mechanical allodynia and thermal hyperalgesia in postnatal day 7 rats and mechanical allodynia in postnatal day 21 rats. A higher dose of morphine was required to produce mechanical allodynia in postnatal day 21 versus 7 rats but this increase was independent of the analgesic efficacy of morphine at these two ages. The present work illustrates the need to examine the phenomenon of hypersensitivity upon opioid withdrawal in the human pediatric population.


Asunto(s)
Hiperalgesia/etiología , Hiperestesia/fisiopatología , Dolor/etiología , Síndrome de Abstinencia a Sustancias/complicaciones , Factores de Edad , Animales , Animales Recién Nacidos , Conducta Animal , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Morfina/toxicidad , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Umbral Sensorial/efectos de los fármacos , Factores de Tiempo
17.
Pain ; 109(3): 409-419, 2004 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-15157702

RESUMEN

Diabetes can induce a bewildering list of sensory changes, including alteration in pain sensitivity. Painful diabetic neuropathy is refractory to most common analgesics. This study examined the effect of a p38alpha MAPK inhibitor, SD-282, on mechanical allodynia, thermal hyperalgesia, and formalin-evoked nociception in streptozotocin-induced diabetic rats. Four-week diabetic rats exhibited mechanical allodynia, decreased mechanical thresholds, and C- and Adelta-fiber mediated thermal hyperalgesia. Mechanical and thermal responses were measured in diabetic rats following acute and repeated intraperitoneal administration of vehicle, 15 or 45 mg/kg SD-282. Mechanical allodynia was reversed by acute and repeated administration of 15 and 45 mg/kg SD-282. Repeated administration of 15 or 45 mg/kg SD-282 prevented the exacerbation of C-, but not Adelta-fiber, mediated thermal hyperalgesia. Repeated administration of 45 mg/kg SD-282 attenuated flinching behaviors during the quiescent period and the second phase of the formalin response in diabetic rats. Acute and repeated administration of 15 or 45 mg/kg SD-282 had no effect on mechanical, thermal or formalin responses in age-matched control rats. These results indicate a potential therapeutic value of p38alpha MAPK inhibitors in the treatment of aberrant pain sensitivity produced by diabetes.


Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Neuropatías Diabéticas/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Neuralgia/tratamiento farmacológico , Analgésicos/farmacocinética , Analgésicos/uso terapéutico , Animales , Neuropatías Diabéticas/enzimología , Neuropatías Diabéticas/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Inhibidores Enzimáticos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/enzimología , Hiperalgesia/fisiopatología , Masculino , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Mielínicas/enzimología , Fibras Nerviosas Amielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/enzimología , Neuralgia/enzimología , Neuralgia/fisiopatología , Nociceptores/efectos de los fármacos , Nociceptores/fisiología , Dimensión del Dolor/efectos de los fármacos , Nervios Periféricos/efectos de los fármacos , Nervios Periféricos/enzimología , Nervios Periféricos/fisiopatología , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos
18.
Pain ; 110(1-2): 281-9, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15275778

RESUMEN

On withdrawal from opioids many patients experience a heightened sensitivity to stimuli and an exaggerated pain response. The phenomenon has been little studied in infants. We present evidence that in postnatal day 7 rats an exaggerated nociceptive ventral root response of spinal cords in vitro and withdrawal-associated thermal hyperalgesia in vivo are dependent on protein kinase C (PKC), and we document the roles of PKC and gamma isozymes. In vitro, the slow ventral root potential (sVRP) is a nociceptive-related response in spinal cord that is depressed by morphine and recovers to levels significantly above control on administration of naloxone. A broad-spectrum PKC antagonist, GF109213X, blocked withdrawal hyperresponsiveness of the sVRP whereas an antagonist specific to Ca(++)-dependent isozymes, Go69076, did not. Consistent with this finding, a specific peptide inhibitor of calcium-independent PKC, but not an inhibitor of calcium-dependent PKC gamma, blocked withdrawal hyperresponsiveness of the sVRP. Similarly, in vivo in 7-day-old rat pups, inhibition of PKC, but not PKC gamma, prevented thermal hyperalgesia precipitated by naloxone at 30 min post-morphine. In contrast, thermal hyperalgesia during spontaneous withdrawal was inhibited by both PKC and gamma inhibitors. The consistency between the in vivo and in vitro findings with respect to naloxone-precipitated withdrawal provides further evidence that the sVRP reflects nociceptive neurotransmission. In addition the difference between naloxone-precipitated and spontaneous withdrawal in vivo suggests that in postnatal day 7 rats, morphine exposure produces an early phase of primary afferent sensitization dependent upon PKC translocation, followed by a later phase involving spinal sensitization mediated by PKC gamma.


Asunto(s)
Morfina/farmacología , Dolor/etiología , Proteína Quinasa C/fisiología , Síndrome de Abstinencia a Sustancias/fisiopatología , Análisis de Varianza , Animales , Animales Recién Nacidos , Conducta Animal , Interacciones Farmacológicas , Inhibidores Enzimáticos/farmacología , Femenino , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/fisiopatología , Técnicas In Vitro , Indoles/farmacología , Masculino , Maleimidas/farmacología , Potenciales de la Membrana/efectos de los fármacos , Naloxona/farmacología , Antagonistas de Narcóticos/farmacología , Narcóticos/farmacología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Péptidos/farmacología , Proteína Quinasa C-epsilon , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiología , Raíces Nerviosas Espinales/citología , Raíces Nerviosas Espinales/efectos de los fármacos , Raíces Nerviosas Espinales/fisiopatología , Síndrome de Abstinencia a Sustancias/enzimología
19.
J Pain ; 3(5): 360-8, 2002 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14622739

RESUMEN

Recent work has supported a key role for spinal cytokines and glial activation in the development and maintenance of persistent neuropathic pain after peripheral nerve injury. This study was undertaken to determine whether the active metabolite of leflunomide (A77 1726), an anti-inflammatory and immunosuppressive agent, could attenuate persistent mechanical allodynia in a rodent L5 spinal nerve transection model. A77 1726 was administered daily intraperitoneally (0.01 to 10 mg/kg) beginning 1 day before nerve transection. In a separate experiment, A77 1726 was administered daily intrathecally (0.001 to 10 microg in 40 microL) beginning 1 hour before nerve transection. Both systemic and centrally administered A77 1726 significantly reduced mechanical allodynia across the time course of the study (P < .05). A77 1726 attenuated glial activation on day 10 after transection at doses that reduced mechanical sensitivity. In addition, central A77 1726 administration decreased spinal expression of major histocompatibility complex class II. Spinal interleukin-6 levels were unaffected by A77 1726 treatment. This study provides further evidence implicating a contribution of spinal glial activation in the development and maintenance of persistent neuropathic pain. Furthermore, this study reports that systemic and central administration of the active metabolite of leflunomide, an immunosuppressive agent used for the treatment of rheumatoid arthritis, produces an antiallodynic action in a rodent mononeuropathy model.

20.
Neurosci Lett ; 366(3): 332-5, 2004 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-15288445

RESUMEN

We have previously found that in post-natal day 7 rats withdrawal from acute and chronic ethanol (EtOH) exposure lowers mechanical thresholds during withdrawal and exacerbates spontaneous pain responses to an inflammatory injury 4 days post-withdrawal. These findings suggested alterations in somatosensory pathways following EtOH exposure during the third trimester developmental equivalent. In this study we wanted to determine whether EtOH exposure during the third trimester equivalent exacerbates mechanical allodynia and thermal hyperalgesia produced by an incisional model of post-operative pain at post-natal day 21. The extent and duration of mechanical allodynia and thermal hyperalgesia following incision was measured and found to be unaffected by prior EtOH exposure.


Asunto(s)
Depresores del Sistema Nervioso Central/farmacología , Etanol/farmacología , Dimensión del Dolor/efectos de los fármacos , Dolor Postoperatorio/fisiopatología , Animales , Animales Recién Nacidos , Depresores del Sistema Nervioso Central/administración & dosificación , Esquema de Medicación , Etanol/administración & dosificación , Hiperalgesia/fisiopatología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
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