Transient Reflexive Pain Responses and Chronic Affective Nonreflexive Pain Responses Associated with Neuroinflammation Processes in Both Spinal and Supraspinal Structures in Spinal Cord-Injured Female Mice.

Central neuropathic pain is not only characterized by reflexive pain responses, but also emotional or affective nonreflexive pain responses, especially in women. Some pieces of evidence suggest that the activation of the neuroimmune system may be contributing to the manifestation of mood disorders in patients with chronic pain conditions, but the mechanisms that contribute to the development and chronicity of CNP and its associated disorders remain poorly understood. This study aimed to determine whether neuroinflammatory factor over-expression in the spinal cord and supraspinal structures may be associated with reflexive and nonreflexive pain response development from acute SCI phase to 12 weeks post-injury in female mice. The results show that transient reflexive responses were observed during the SCI acute phase associated with transient cytokine overexpression in the spinal cord. In contrast, increased nonreflexive pain responses were observed in the chronic phase associated with cytokine overexpression in supraspinal structures, especially in mPFC. In addition, results revealed that besides cytokines, the mPFC showed an increased glial activation as well as CX3CL1/CX3CR1 upregulation in the neurons, suggesting the contribution of neuron-glia crosstalk in the development of nonreflexive pain responses in the chronic spinal cord injury phase.

Astrocyte reactivity in the glia limitans superficialis of the rat medial prefrontal cortex following sciatic nerve injury.

The glia limitans superficialis (GLS) on the rodent cortical surface consists of astrocyte bodies intermingled with their cytoplasmic processes. Many studies have observed astrocyte reactivity in the medial prefrontal cortex (mPFC) parenchyma induced by a peripheral nerve injury, while the response of GLS astrocytes is still not fully understood. The aim of our study was to identify the reactivity of rat GLS astrocytes in response to sciatic nerve compression (SNC) over different time periods. The alteration of GLS astrocyte reactivity was monitored using immunofluorescence (IF) intensities of glial fibrillary acidic protein (GFAP), glutamine synthetase (GS), and NFκBp65. Our results demonstrated that SNC induced GLS astrocyte reactivity seen as increased intensities of GFAP-IF, and longer extensions of cytoplasmic processes into lamina I. First significant increase of GFAP-IF was observed on post-operation day 7 (POD7) after SNC with further increases on POD14 and POD21. In contrast, dynamic alteration of the extension of cytoplasmic processes into lamina I was detected as early as POD1 and continued throughout the monitored survival periods of both sham and SNC operations. The reactivity of GLS astrocytes was not associated with their proliferation. In addition, GLS astrocytes also displayed a significant decrease in GS immunofluorescence (GS-IF) and NFκB immunofluorescence (NFκB-IF) in response to sham and SNC operation compared with naïve control rats. These results suggest that damaged peripheral tissues (following sham operation as well as peripheral nerve lesions) may induce significant changes in GLS astrocyte reactivity. The signaling mechanism from injured peripheral tissue and nerve remains to be elucidated.

Polyphenolic grape stalk and coffee extracts attenuate spinal cord injury-induced neuropathic pain development in ICR-CD1 female mice.

More than half of spinal cord injury (SCI) patients develop central neuropathic pain (CNP), which is largely refractory to current treatments. Considering the preclinical evidence showing that polyphenolic compounds may exert antinociceptive effects, the present work aimed to study preventive effects on SCI-induced CNP development by repeated administration of two vegetal polyphenolic extracts: grape stalk extract (GSE) and coffee extract (CE). Thermal hyperalgesia and mechanical allodynia were evaluated at 7, 14 and 21 days postinjury. Then, gliosis, ERK phosphorylation and the expression of CCL2 and CX3CL1 chemokines and their receptors, CCR2 and CX3CR1, were analyzed in the spinal cord. Gliosis and CX3CL1/CX3CR1 expression were also analyzed in the anterior cingulate cortex (ACC) and periaqueductal gray matter (PAG) since they are supraspinal structures involved in pain perception and modulation. GSE and CE treatments modulated pain behaviors accompanied by reduced gliosis in the spinal cord and both treatments modulated neuron-glia crosstalk-related biomolecules expression. Moreover, both extracts attenuated astrogliosis in the ACC and PAG as well as microgliosis in the ACC with an increased M2 subpopulation of microglial cells in the PAG. Finally, GSE and CE prevented CX3CL1/CX3CR1 upregulation in the PAG, and modulated their expression in ACC. These findings suggest that repeated administrations of either GSE or CE after SCI may be suitable pharmacologic strategies to attenuate SCI-induced CNP development by means of spinal and supraspinal neuroinflammation modulation.