RESUMEN
INTRODUCTION: HIV infection is associated with chronic pain states, including sensory neuropathy, which affects greater than 40% of patients. OBJECTIVES AND METHODS: To determine the impact of HIV-Tat induction on nociceptive behaviour in female mice conditionally expressing HIV Tat1-86 protein through a doxycycline (DOX)-driven glial fibrillary acidic protein promoter, intraepidermal nerve fibre density and immune cell activation in the dorsal root ganglion (DRG) and spinal cord were assessed by immunohistochemistry. Mice were assessed for mechanical and thermal sensitivity for 9 weeks using von-Frey and Hargreaves tests. RESULTS: Intraepidermal nerve fibre density was significantly reduced after 6 weeks of Tat induction, similar to sensory neuropathy seen in clinical HIV infection. Tat induction through DOX caused a significant reduction in paw withdrawal thresholds in a time-dependent manner starting the 4th week after Tat induction. No changes in paw withdrawal latencies were seen in Tat(-) control mice lacking the tat transgene. Although reductions in paw withdrawal thresholds increased throughout the study, no significant change in spontaneous motor activity was observed. Spinal cord (cervical and lumbar), DRG, and hind paw skin were collected at 8 days and 6 weeks after Tat induction. HIV-Tat mRNA expression was significantly increased in lumbar DRG and skin samples 8 days after DOX treatment. Tat induced a significant increase in the number of Iba-1 positive cells at 6 weeks, but not after 8 days, of exposure. No differences in glial fibrillary acidic protein immunoreactivity were observed. CONCLUSION: These results suggest that Tat protein contributes to painful HIV-related sensory neuropathy during the initial stages of the pathogenesis.
RESUMEN
HIV-associated sensory neuropathy (HIV-SN) is the most frequent manifestation of HIV disease. It often presents with significant neuropathic pain and is associated with previous exposure to neurotoxic nucleoside reverse transcriptase inhibitors. However, HIV-SN prevalence remains high even in resource-rich settings where these drugs are no longer used. Previous evidence suggests that exposure to indinavir, a protease inhibitor commonly used in antiretroviral therapy, may link to elevated HIV-SN risk. Here, we investigated whether indinavir treatment was associated with the development of a "dying back" axonal neuropathy and changes in pain-relevant limb withdrawal and thigmotactic behaviours. After 2 intravenous injections of indinavir (50 mg/kg, 4 days apart), adult rats developed hind paw mechanical hypersensitivity, which peaked around 2 weeks post first injection (44% reduction from baseline). At this time, animals also had (1) significantly changed thigmotactic behaviour (62% reduction in central zone entries) comparing with the controls and (2) a significant reduction (45%) in hind paw intraepidermal nerve fibre density. Treatment with gabapentin, but not amitriptyline, was associated with a complete attenuation of hind paw mechanical hypersensitivity observed with indinavir treatment. Furthermore, we found a small but significant increase in microglia with the effector morphology in the lumbar spinal dorsal horn in indinavir-treated animals, coupled with significantly increased expression of phospho-p38 in microglia. In summary, we have reported neuropathic pain-related sensory and behavioural changes accompanied by a significant loss of hind paw skin sensory innervation in a rat model of indinavir-induced peripheral neuropathy that is suitable for further pathophysiological investigation and preclinical evaluation of novel analgesics.
Asunto(s)
Infecciones por VIH/inducido químicamente , Infecciones por VIH/complicaciones , Inhibidores de la Proteasa del VIH/toxicidad , Indinavir/toxicidad , Neuralgia/etiología , Umbral del Dolor/efectos de los fármacos , Aminas/uso terapéutico , Analgésicos/uso terapéutico , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Proteínas de Unión al Calcio/metabolismo , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Gabapentina , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ganglios Espinales/patología , Regulación de la Expresión Génica/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Hiperalgesia/etiología , Masculino , Metacarpo/efectos de los fármacos , Metacarpo/inervación , Proteínas de Microfilamentos/metabolismo , Microglía/efectos de los fármacos , Microglía/metabolismo , Neuralgia/complicaciones , Neuralgia/tratamiento farmacológico , Neuralgia/patología , Dimensión del Dolor , Estimulación Física/efectos adversos , Ratas , Ratas Wistar , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patología , Estadísticas no Paramétricas , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Understanding the non-sensory components of the pain experience is crucial to developing effective treatments for pain conditions. Chronic pain is associated with increased incidence of anxio-depressive disorders, and patients often report feelings of vulnerability which can decrease quality of life. In animal models of pain, observation of behaviours such as thigmotaxis can be used to detect such affective disturbances by exploiting the influence of nociceptive stimuli on the innate behavioural conflict between exploration of a novel space and predator avoidance behaviour. This study investigates whether acute and repeated bladder inflammation in adult female Wistar rats increases thigmotactic behaviour in the open field paradigm, and aims to determine whether this correlates with activation in the central amygdala, as measured by c-Fos immunoreactivity. Additionally, up-regulation of inflammatory mediators in the urinary bladder was measured using RT-qPCR array featuring 92 transcripts to examine how local mediators change under experimental conditions. We found acute but not repeated turpentine inflammation of the bladder increased thigmotactic behaviour (decreased frequency of entry to the inner zone) in the open field paradigm, a result that was also observed in the catheter-only instrumentation group. Decreases in locomotor activity were also observed in both models in turpentine and instrumentation groups. No differences were observed in c-Fos activation, although a general increased in activation along the rostro-caudal axis was seen. Inflammatory mediator up-regulation was greatest following acute inflammation, with CCL12, CCL7, and IL-1ß significantly up-regulated in both conditions when compared to naïve tissue. These results suggest that acute catheterisation, with or without turpentine inflammation, induces affective alterations detectable in the open field paradigm accompanied by up-regulation of multiple inflammatory mediators.