Pain
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Below-level central neuropathic pain (CNP) affects a large proportion of spinal cord injured individuals. To better define the dynamic changes of the spinal cord neural network contributing to the development of CNP after spinal cord injury (SCI), we characterized the morphological and behavioral correlates of CNP in female C57BL/6 mice after a moderate T11 contusion SCI (50 kdyn) and the influence of moderate physical activity. Compared with sham-operated animals, injured mice developed mechanical allodynia 2 weeks post injury when tested with small-diameter von Frey hair filaments (0.16 g and 0.4 g filament), but presented hyporesponsiveness to noxious mechanical stimuli (1.4 g filament). ⋯ Analysis of IB4-labeled nonpeptidergic sensory fibers revealed no differences between experimental groups. Abnormalities in temperature sensation were not influenced by physical activity. Thus, treadmill training partially resolves signs of below-level CNP after SCI and modulates the density of CGRP-labeled fibers.
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Clinical studies show that chronic pain can spread to adjacent or even distant body regions in some patients. However, little is known about how this happens. In this study, we found that partial infraorbital nerve transection (p-IONX) in MRL/MPJ mice induced not only marked and long-lasting orofacial thermal hyperalgesia but also thermal hyperalgesia from day 3 postoperatively (PO) and tactile allodynia from day 7 PO in bilateral hind paws. ⋯ In addition, microglial activation after p-IONX transmitted caudally from the Vc in the medulla to lumber dorsal horn in a time-dependent manner. Inhibition of microglial activation by minocycline at early but not late stage after p-IONX postponed and attenuated pain sensitization in the hind paw. These results indicate that neuropathic pain after p-IONX in MRL/MPJ mice spreads from the orofacial region to distant somatic regions and that a rostral-caudal transmission of central sensitization in the spinal cord is involved in the spreading process of pain hypersensitivity.
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The enzymatic activity of protein tyrosine kinase Src is subjected to the regulation by C-terminal Src kinase (CSK) and protein tyrosine phosphatases (PTPs). Aberrant Src activation in the spinal cord dorsal horn is pivotal for the induction and development of nociceptive behavioral sensitization. In this study, we found that paxillin, one of the well-characterized cell adhesion components involved in cell migration and survival, integrated CSK and PTPs' signaling to regulate Src-dependent nociceptive plasticity. ⋯ In complete Freund's adjuvant-injected mice, viral expression of phosphomimicking paxillin mutant to resume CSK synaptic localization repressed Src hyperactivity. Meanwhile, this phosphomimicking paxillin mutant blunted NMDA receptor-mediated synaptic transmission and alleviated chronic inflammatory pain. These data showed that PTPs-mediated dephosphorylation of paxillin at Tyr118 was involved in the modification of nociceptive plasticity through CSK-Src signaling.
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Trigeminal neuropathic pain is a well-recognized complication of the demyelinating disease multiple sclerosis (MS). However, the mechanisms underlying MS-related trigeminal neuropathic pain are poorly understood. This can be attributed, at least in part, to the lack of an animal model that exhibits trigeminal pathology similar to that described in MS. ⋯ We also observe demyelination of the intra- and extra-pontine aspects of the trigeminal sensory root and the spinal trigeminal tract. This is the first study to show orofacial sensory disturbances and trigeminal demyelination in EAE. Collectively, our data suggest that EAE may be a useful model for understanding MS-related trigeminal neuropathic pain conditions such as trigeminal neuralgia.