Experimental neurology
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Experimental neurology · Oct 2013
Burn injury-induced mechanical allodynia is maintained by Rac1-regulated dendritic spine dysgenesis.
Although nearly 11 million individuals yearly require medical treatment due to burn injuries and develop clinically intractable pain, burn injury-induced pain is poorly understood, with relatively few studies in preclinical models. To elucidate mechanisms of burn injury-induced chronic pain, we utilized a second-degree burn model, which produces a persistent neuropathic pain phenotype. Rats with burn injury exhibited reduced mechanical pain thresholds ipsilateral to the burn injury. ⋯ Heat hyperalgesia testing produced variable results, as expected from previous studies of this model of second-degree burn injury in rats. Administration of Rac1-inhibitor, NSC23766, attenuated dendritic spine dysgenesis, decreased mechanical allodynia and electrophysiological signs of burn-induced neuropathic pain. These results support two related implications: that the presence of abnormal dendritic spines contributes to the maintenance of neuropathic pain, and that therapeutic targeting of Rac1 signaling merits further investigation as a novel strategy for pain management after burn injury.
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Experimental neurology · Oct 2013
A re-assessment of the effects of treatment with a non-steroidal anti-inflammatory (ibuprofen) on promoting axon regeneration via RhoA inhibition after spinal cord injury.
This study was undertaken as part of the NIH "Facilities of Research Excellence-Spinal Cord Injury" project to support independent replication of published studies. Here, we repeat key parts of a study reporting that rats treated with ibuprofen via subcutaneous minipump exhibited greater recovery of motor function and enhanced axonal growth after spinal cord injury. We carried out 3 separate experiments in which young adult female Sprague-Dawley rats received dorsal over-hemisections at T6-T7, and then were implanted with osmotic minipumps for subcutaneous delivery of ibuprofen or saline. ⋯ Rats that received Ibuprofen did not demonstrate statistically significant improvements in bladder function. Quantitative analyses of CST and 5HT axon distribution also did not reveal differences between ibuprofen-treated and control rats. Taken together, our results only partially replicate the findings that treatment with ibuprofen improves motor function after SCI but fail to replicate findings regarding enhanced axon growth.
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Experimental neurology · Oct 2013
Endogenous descending facilitation and inhibition differ in control of formalin intramuscularly induced persistent muscle nociception.
In conscious rats, intramuscular injection of 2.5% formalin into the gastrocnemius muscle, at volumes between 25 and 200 μl, evoked dose-dependent biphasic persistent flinching activities: phase 1 (0-10 min) and phase 2 (10-60 min). During this intramuscular formalin-induced ipsilateral muscle nociception, bilateral secondary mechanical hyperalgesia and heat hypoalgesia assessed by measuring thresholds of paw withdrawal reflex to noxious mechanical and heat stimuli were observed (P<0.05). Lesion of either the ipsilateral dorsal funiculus (DF) or contralateral thalamic mediodorsal (MD) nucleus significantly alleviated the formalin-induced flinches in both phase 1 and phase 2 of the behavioral response, and blocked the occurrence of secondary mechanical hyperalgesia, but not heat hypoalgesia. ⋯ By contrast, microinjection of GABA into the thalamic VM nucleus significantly enhanced the formalin-induced nociceptive behavior in the late part (30-60 min) of phase 2, and the bilateral secondary heat hypoalgesia was temporarily prevented (P<0.05). The present study demonstrates that intramuscular formalin evokes biphasic muscle nociception, and that bilateral secondary mechanical hyperalgesia and heat hypoalgesia are differentially controlled by endogenous descending facilitation and inhibition respectively. It is further suggested that thalamic MD nucleus and VM nucleus constitute an endogenous discriminative, modulatory system that exerts, via pathways in the DF and DLF, descending facilitatory and inhibitory actions on responses to peripheral afferent activity evoked by noxious mechanical and heat stimulation.
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Experimental neurology · Oct 2013
Sensitization of sodium channels by cystathionine β-synthetase activation in colon sensory neurons in adult rats with neonatal maternal deprivation.
The pathogenesis of pain in irritable bowel syndrome (IBS) is poorly understood and treatment remains difficult. We have previously reported that TTX-resistant (TTX-R) sodium channels in colon-specific dorsal root ganglion (DRG) neurons were sensitized and the expression of the endogenous hydrogen sulfide producing enzyme cystathionine β-synthetase (CBS) was upregulated in a rat model of visceral hypersensitivity induced by neonatal maternal deprivation (NMD). However, the detailed molecular mechanism for activation of sodium channels remains unknown. This study was designed to examine roles for CBS-H₂S signaling in sensitization of sodium channels in a previously validated rat model of IBS. ⋯ These data suggest that sensitization of sodium channels of colon DRG neurons in NMD rats is most likely mediated by CBS-H₂S signaling, thus identifying a potential target for treatment for chronic visceral pain in patients with IBS.
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Experimental neurology · Oct 2013
The role of α₂ adrenoceptor in mediating noradrenaline action in the ventrolateral orbital cortex on allodynia following spared nerve injury.
The present study examined the role of α₂ adrenoceptor in mediating noradrenaline action in the ventrolateral orbital cortex (VLO) on allodynia induced by spared nerve injury (SNI) in the rat. The mechanical paw withdrawal threshold (PWT) was measured using von-Frey filaments. Microinjection of noradrenaline (1, 2, 4 μg in 0.5 μl) into the VLO, contralateral to the site of nerve injury, reduced allodynia; PWT increased in a dose-dependent manner. ⋯ Furthermore, administration of γ-aminobutyric acid A (GABAA) receptor antagonist bicuculline or picrotoxin to the VLO significantly enhanced clonidine-induced inhibition of allodynia, while GABAA receptor agonist muscimol or THIP (2,5,6,7-retrahydroisoxazolo(5,4-c)pyridine-3-ol hydrochloride) attenuated clonidine-induced inhibition. These results suggest that noradrenaline acting in the VLO can potentially reduce allodynia induced by SNI, and this effect is mediated by α₂ adrenoceptor. Moreover, GABAergic disinhibition may participate in α₂ receptor mediating effects in neuropathic pain in the central nervous system.