RESUMEN
BACKGROUND: Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects. Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet. RESULTS: Rats fed the AHF diet developed visceral pain-like behaviors detectable by week 3 and reached a maximum at week 5 that persists as long as the diet is maintained. Rats with AHF induced chronic pancreatitis were treated with LY3038404 HCl (10 mg/kg, orally, twice a day for 9 days). The treated animals demonstrated significantly alleviated pain related behaviors after 3 days of dosing, including increased paw withdrawal thresholds (PWT), prolonged abdominal withdrawal latencies (ABWL), and decreased nocifensive responses to noxious 44°C hotplate stimuli. Terminal histological analysis of pancreatic tissue sections from the AHF chronic pancreatitis animals demonstrated extensive injury, including a global pancreatic gland degeneration (cellular atrophy), vacuolization (fat deposition), and fibrosis. After the LY3038404 HCl treatment, pancreatic tissue was significantly protected from severe damage and fibrosis. LY3038404 HCl affected neither open field exploratory behaviors nor dark/light box preferences as measures of higher brain and motor functions. CONCLUSION: LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.
Asunto(s)
Agonistas de Receptores de Cannabinoides/uso terapéutico , Pancreatitis Crónica/complicaciones , Receptor Cannabinoide CB1/agonistas , Dolor Visceral/tratamiento farmacológico , Dolor Visceral/etiología , Alcoholes/toxicidad , Animales , Proliferación Celular/efectos de los fármacos , Adaptación a la Oscuridad/efectos de los fármacos , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Fibrosis/etiología , Fibrosis/patología , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/etiología , Masculino , Umbral del Dolor/efectos de los fármacos , Pancreatitis Crónica/etiología , Pancreatitis Crónica/patología , Ratas , Ratas Endogámicas F344 , Tiempo de Reacción/efectos de los fármacos , Índice de Severidad de la EnfermedadRESUMEN
A thermal preference task was used to assess the effects of sleep deprivation on nociceptive behavior using hot and cool stimuli. The thermal preference apparatus allowed male rats to move freely from a hot thermal plate (44.7°C) to an adjacent plate at neutral (33.5°C) or cold temperatures (1.3-11°C). Investigators recorded occupancy on the colder side, frequency of movements between the 2 compartments, and first escape latency from the cold side. Parametric analysis of thermal preference indicated that behavioral allocation was related to temperature ranges previously associated with activation of thermal nociceptors. A 50% occupancy rate was determined from a stimulus-response function identifying 1.3°C vs. 44.7°C as optimal temperatures. This temperature combination was then used to test the effects of sleep deprivation for 48h using the pedestal-over-water method on response allocation to the 2 temperature zones. Sleep deprivation decreased time spent on the cooled plate. Cumulative occupancy indicated differential effects for sleep deprivation with the rats preferring to remain on the hot side vs. the cold side, suggesting that sleep deprivation increased the nociceptive properties of the cold stimulus.
Asunto(s)
Dimensión del Dolor/métodos , Umbral del Dolor/fisiología , Dolor/fisiopatología , Privación de Sueño/fisiopatología , Sensación Térmica/fisiología , Animales , Frío/efectos adversos , Calor/efectos adversos , Masculino , Fibras Nerviosas Mielínicas/fisiología , Fibras Nerviosas Amielínicas/fisiología , Nociceptores/fisiología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/fisiologíaRESUMEN
BACKGROUND: Unilateral constrictive sciatic nerve injury (uCCI) is a common neuropathic pain model. However, the bilateral constrictive injury (bCCI) model is less well studied, and shows unique characteristics. In the present study, we sought to correlate effects of bCCI on nocifensive responses to cold and mechanical stimuli with selected dorsal horn anatomic markers. bCCI or sham ligation of both rat sciatic nerves were followed up to 90 days of behavioural testing. Additional rats sacrificed at 15, 30 and 90 days were used for anatomic analyses. Behavioural tests included hindpaw withdrawal responses to topical acetone, cold plate testing, an operant thermal preference task and hindpaw withdrawal thresholds to mechanical probing. RESULTS: All nocifensive responses to cold increased and remained enhanced for >45 days. Mechanical withdrawal thresholds decreased for 25 days only. Densitometric analyses of immunoperoxidase staining in the superficial dorsal horn at L4-5 revealed decreased cholecystokinin (CCK) staining at all times after bCCI, decreased mu opiate receptor (MOR) staining, maximal at 15 days, increased neuropeptide Y (NPY) staining only at days 15 and 30, and increased neurokinin-1 receptor (NK-1R) staining at all time points, maximal at 15 days. Correlation analyses at 45 days post-bCCI, were significant for individual rat nocifensive responses in each cold test and CCK and NK-1R, but not for MOR or NPY. CONCLUSIONS: These results confirm the usefulness of cold testing in bCCI rats, a new approach using CCI to model neuropathic pain, and suggest a potential value of studying the roles of dorsal horn CCK and substance P in chronic neuropathic pain. Compared to human subjects with neuropathic pain, responses to cold stimuli in rats with bCCI may be a useful model of neuropathic pain.
Asunto(s)
Dimensión del Dolor/métodos , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Células del Asta Posterior/metabolismo , Neuropatía Ciática/metabolismo , Neuropatía Ciática/fisiopatología , Acetona/farmacología , Analgésicos/farmacología , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Colecistoquinina/metabolismo , Enfermedad Crónica , Frío/efectos adversos , Modelos Animales de Enfermedad , Femenino , Lateralidad Funcional/fisiología , Hiperalgesia/diagnóstico , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Inmunohistoquímica , Ligadura , Neuropéptido Y/metabolismo , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Células del Asta Posterior/citología , Valor Predictivo de las Pruebas , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/metabolismo , Receptores Opioides mu/metabolismo , Reflejo/efectos de los fármacos , Reflejo/fisiología , Neuropatía Ciática/diagnósticoRESUMEN
The role of spinal cord mu-opioid receptor (MOR)-expressing dorsal horn neurons in nociception and morphine analgesia is incompletely understood. Using intrathecal dermorphin-saporin (Derm-sap) to selectively destroy MOR-expressing dorsal horn neurons, we sought to determine the role of these neurons in (1) normal baseline reflex nocifensive responses to noxious thermal stimulation (hotplate, tail flick) and to persistent noxious chemical stimulation (formalin) and (2) the antinociceptive activity of intrathecal and systemic morphine in the same tests. Lumbar intrathecal Derm-sap (500 ng) produced (1) partial loss of lamina II MOR-expressing dorsal horn neurons, (2) no effect on MOR-expressing dorsal root ganglion neurons, and (3) no change in baseline tail-flick and hotplate reflex nocifensive responses. Derm-sap treatment attenuated the antinociceptive action of both intrathecal and systemic morphine on hotplate responses. Derm-sap treatment had two effects in the formalin test: (1) increased baseline nocifensive responding and (2) reduced antinociceptive action of systemic morphine. We conclude that MOR-expressing dorsal horn neurons (1) are not essential for determining nocifensive reflex responsiveness to noxious thermal stimuli, (2) are necessary for full antinociceptive action of morphine (intrathecal or systemic) in these tests, and (3) play a significant role in the endogenous modulation of reflex nocifensive responses to persistent pain in the formalin test. Thus, one would predict that altering the activity of MOR-expressing dorsal horn neurons would be antinociceptive and of interest in the search for new approaches to management of chronic pain.
Asunto(s)
Analgésicos/uso terapéutico , Morfina/uso terapéutico , Dolor/metabolismo , Células del Asta Posterior/metabolismo , Receptores Opioides mu/biosíntesis , Analgésicos/farmacología , Animales , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Masculino , Morfina/farmacología , Dolor/tratamiento farmacológico , Dolor/genética , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Células del Asta Posterior/efectos de los fármacos , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Receptores Opioides mu/agonistas , Receptores Opioides mu/genéticaRESUMEN
REM sleep deprivation (REMSD) has been shown to increase rates of negatively reinforced operant behavior, but not operant responding maintained by positive reinforcement. The reason for this differential effect is currently unknown. We hypothesize that REMSD can increase sensitivity to noxious stimuli. In the present study, we sought to determine if REMSD was associated with a change in response to noxious heat (i.e., altered nociceptive sensitivity). Two groups of rats, aged 6 and 22 months, were subjected to hotplate algesia testing at two different temperatures (44 and 52 degrees C). Initially, baseline numbers of responses and total response time were obtained at 44 degrees C. Animals then were exposed to 48 h of REMSD or control conditions. The frequency and duration of hindpaw responses (licking and guarding) increased for young animals only after REMSD and none of the control conditions. Old rats showed increased duration of nocifensive responding after REMSD and tank control conditions without a change in the number of responses at 44 degrees C. Latency to first nocifensive response was significantly longer in the 44 degrees C hotplate tests, but decreased to levels observed throughout the 52 degrees C hotplate tests following REMSD and TC conditions. These findings suggest that REMSD increases nociceptive sensitivity under conditions of sustained, selective C nociceptor activation (42 degrees C), but not under conditions of phasic A-delta activation (52 degrees C). The findings also indicate that age can be a significant variable in REMSD studies.