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1.
Brain Behav Immun ; 120: 471-487, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38925417

RESUMEN

Activity-induced muscle pain increases interleukin-1ß (IL-1ß) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1ß in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1ß and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1ß activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia. We tested the effect of intrathecal or intramuscular injection of BDNF-Tropomyosin receptor kinase B (TrkB) inhibitors, ANA-12 or TrkB-Fc, on development of activity-induced pain. Both inhibitors prevented the hyperalgesia when given before or 24hr after induction of the model in male but not female mice. BDNF messenger ribonucleic acid (mRNA) and protein were significantly increased in dorsal root ganglion (DRG) 24hr after induction of the model in both male and female mice. Blockade of IL-1ß in muscle had no effect on the increased BNDF mRNA observed in the activity-induced pain model, while IL-1ß applied to cultured DRG significantly induced BDNF expression, suggesting IL-1ß is sufficient but not necessary to induce BNDF. Thus, fatigue metabolites, combined with IL-1ß, upregulate BDNF in primary DRG neurons in both male and female mice, but contribute to activity-induced pain only in males.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo , Ganglios Espinales , Hiperalgesia , Interleucina-1beta , Mialgia , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Masculino , Femenino , Ratones , Ganglios Espinales/metabolismo , Interleucina-1beta/metabolismo , Mialgia/metabolismo , Hiperalgesia/metabolismo , Ratones Endogámicos C57BL , Receptor trkB/metabolismo , Músculo Esquelético/metabolismo , Factores Sexuales , Caracteres Sexuales , Benzamidas/farmacología , Células Receptoras Sensoriales/metabolismo , Células Receptoras Sensoriales/efectos de los fármacos , Azepinas
2.
bioRxiv ; 2023 Nov 02.
Artículo en Inglés | MEDLINE | ID: mdl-37961342

RESUMEN

Activity-induced muscle pain increases release of interleukin-1ß (IL-1ß) in muscle macrophages and the development of pain is prevented by blockade of IL-1ß. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1ß and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1ß, which subsequently activate sensory neurons to secrete BDNF. To test this hypothesis, we used an animal model of activity-induced pain induced by repeated intramuscular acidic saline injections combined with fatiguing muscle contractions. Intrathecal or intramuscular injection of inhibitors of BDNF-Tropomyosin receptor kinase B (TrkB) signaling, ANA-12 or TrkB-Fc, reduced the decrease in muscle withdrawal thresholds in male, but not in female, mice when given before or 24hr after, but not 1 week after induction of the model. BDNF messenger ribonucleic acid (mRNA) was significantly increased in L4-L6 dorsal root ganglion (DRG), but not the spinal dorsal horn or gastrocnemius muscle, 24hr after induction of the model in either male or female mice. No changes in TrkB mRNA or p75 neurotrophin receptor mRNA were observed. BDNF protein expression via immunohistochemistry was significantly increased in L4-L6 spinal dorsal horn and retrogradely labelled muscle afferent DRG neurons, at 24hr after induction of the model in both sexes. In cultured DRG, fatigue metabolites combined with IL-1ß significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1ß, BDNF from primary DRG neurons and contribute to activity-induced muscle pain only in males, while there were no sex differences in the changes in expression observed in BDNF.

3.
Pain ; 164(8): 1775-1782, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36877823

RESUMEN

ABSTRACT: Rigorous experimental design with transparent reporting in biomedical science reduces risk of bias and allows for scientists to judge the quality of the research. Basic factors of rigor such as blinding, randomization, power analysis, and inclusion of both sexes impact the reproducibility by reducing experimental bias. We designed a systematic study to analyze basic factors of rigor, inclusion of sex, and whether data were analyzed or disaggregated by sex over the past 10 years in the journal PAIN . Studies that included humans reported randomization in 81%, blinding in 48%, and the use of a power analysis calculation in 27% over the past 10 years. Studies that included mice reported randomization in 35%, blinding in 70%, and the use of a power analysis in 9%. Studies that included rats reported randomization in 38%, blinding in 63%, and the use of power analysis in 12%. This study also found that human studies consistently included both sexes over the past decade, but less than 20% of data were disaggregated or analyzed for sex differences. Although mouse and rat studies predominately used males only, there has been a slight increase in inclusion of both sexes over the past few years. Justification for single-sex studies was below 50% in both human and rodent data. In both human and animal studies, transparency in reporting of experimental design and inclusion of both sexes should be considered standard practice and will result in improved quality and reproducibility of published research.


Asunto(s)
Proyectos de Investigación , Caracteres Sexuales , Femenino , Humanos , Masculino , Animales , Ratones , Ratas , Reproducibilidad de los Resultados , Sesgo
4.
Pain ; 164(11): 2463-2476, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37326644

RESUMEN

ABSTRACT: The propensity for breast cancer to metastasize to bone is coupled to the most common complaint among breast cancer patients: bone pain. Classically, this type of pain is treated using escalating doses of opioids, which lack long-term efficacy due to analgesic tolerance, opioid-induced hypersensitivity, and have recently been linked to enhanced bone loss. To date, the molecular mechanisms underlying these adverse effects have not been fully explored. Using an immunocompetent murine model of metastatic breast cancer, we demonstrated that sustained morphine infusion induced a significant increase in osteolysis and hypersensitivity within the ipsilateral femur through the activation of toll-like receptor-4 (TLR4). Pharmacological blockade with TAK242 (resatorvid) as well as the use of a TLR4 genetic knockout ameliorated the chronic morphine-induced osteolysis and hypersensitivity. Genetic MOR knockout did not mitigate chronic morphine hypersensitivity or bone loss. In vitro studies using RAW264.7 murine macrophages precursor cells demonstrated morphine-enhanced osteoclastogenesis that was inhibited by the TLR4 antagonist. Together, these data indicate that morphine induces osteolysis and hypersensitivity that are mediated, in part, through a TLR4 receptor mechanism.


Asunto(s)
Neoplasias de la Mama , Osteólisis , Ratones , Humanos , Animales , Femenino , Morfina/farmacología , Receptor Toll-Like 4/genética , Osteólisis/inducido químicamente , Osteólisis/tratamiento farmacológico , Modelos Animales de Enfermedad , Analgésicos Opioides/uso terapéutico , Dolor/tratamiento farmacológico
5.
Front Pharmacol ; 12: 632757, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33953672

RESUMEN

The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.

6.
J Appl Genet ; 61(4): 567-570, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32794098

RESUMEN

Niemann-Pick C1 (NPC1) mouse models show neurofibrillary tangles as do human patients. A previous study in NPC1/tau double-null mutant mice showed that tau knockout nulls and heterozygotes unexpectedly had decreased survival when compared with NPC1 single mutants (Pacheco et al., Hum Molec Genetics 18:956-965, 2009). This was done in a null model of NPC1 (Npc1-/-). We have extended these results to a hypomorphic model (Npc1nmf164) and additionally studied tau phosphorylation, which has not been previously done in a tau heterozygote. As before, NPC1/tau double-mutant mice had shortened survival when compared with the NPC1 single mutant. Tau dosage was not affected by the Npc1 mutation. The increased phosphorylation of tau-ser396 previously noted in NPC1 mouse models was also present, but unaffected by the tau knockout, indicating that changes in tau phosphorylation are not the cause of decreased survival in NPC1/tau double mutants. Thus, the reason for shortened survival of NPC1 mouse models with concomitant tau haploinsufficiency is uncertain.


Asunto(s)
Haploinsuficiencia/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Enfermedad de Niemann-Pick Tipo C/genética , Proteínas tau/genética , Animales , Modelos Animales de Enfermedad , Heterocigoto , Humanos , Ratones , Ratones Noqueados , Mutación/genética , Proteína Niemann-Pick C1 , Enfermedad de Niemann-Pick Tipo C/patología , Fosforilación
7.
J Autism Dev Disord ; 34(4): 433-8, 2004 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-15449518

RESUMEN

Although clinicians typically assume that feeding problems co-exist with a diagnosis of autism, no previous research has compared the eating behavior of children with autism to typically developing children. This study compared caregiver report of eating problems of children with and without autism on a standardized questionnaire. The questionnaire included items pertaining to food refusal and acceptance patterns as well as food presentation requirements. Caregivers were also asked to complete a food inventory that indicated the number of foods eaten within each food group for both the child and the family. Results indicated children with autism have significantly more feeding problems and eat a significantly narrower range of foods than children without autism.


Asunto(s)
Trastorno Autístico , Conducta Alimentaria , Cuidadores , Niño , Preescolar , Métodos de Alimentación , Femenino , Preferencias Alimentarias , Humanos , Masculino , Encuestas y Cuestionarios
8.
Res Dev Disabil ; 25(1): 57-66, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-14733976

RESUMEN

Researchers have been placing an increased importance on discovering what variables contribute to better prognosis during behavioral interventions for children with autism. This article preliminarily identifies sleep problems that may exacerbate symptoms of autism; thus, possibly influencing effectiveness of daytime interventions. A data-base of parent report of sleep problems of children with autism (N=55), ranging from 5 to 12 years of age (M=8.2 years) was evaluated. Results suggested that fewer hours of sleep per night predicted overall autism scores and social skills deficits. Similarly, stereotypic behavior was predicted by fewer hours of sleep per night and screaming during the night. Increased sensitivity to environmental stimuli in the bedroom and screaming at night predicted communication problems. Finally, sensitivity to environmental stimuli in the bedroom also predicted fewer developmental sequence disturbances. The results indicate that sleep problems and the diagnostic characteristics of autism may be related. However, future research must be completed to determine the specific relationship.


Asunto(s)
Trastorno Autístico/diagnóstico , Trastornos del Sueño-Vigilia/diagnóstico , Trastorno Autístico/epidemiología , Trastorno Autístico/psicología , Trastorno Autístico/terapia , Terapia Conductista , Niño , Preescolar , Trastornos de la Comunicación/diagnóstico , Trastornos de la Comunicación/epidemiología , Trastornos de la Comunicación/psicología , Trastornos de la Comunicación/terapia , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Pronóstico , Análisis de Regresión , Factores de Riesgo , Privación de Sueño/complicaciones , Privación de Sueño/epidemiología , Trastornos del Sueño-Vigilia/epidemiología , Trastornos del Sueño-Vigilia/psicología , Trastornos del Sueño-Vigilia/terapia , Medio Social , Socialización , Resultado del Tratamiento
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