The journal of pain : official journal of the American Pain Society
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Chronic pain after spinal cord injury represents a therapeutic challenge. Progesterone, a neuroprotective steroid, has been shown to modulate nociceptive thresholds, whereas its effect on neuropathic pain needs to be further explored. In this study, we evaluated whether progesterone could ameliorate pain-associated behaviors in animals subjected to a spinal cord hemisection. The development of mechanical and cold allodynia was assessed in injured male rats treated with daily injections of progesterone or vehicle. The expression of N-methyl-D-aspartate receptor (NMDAR) subunits, protein kinase C gamma (PKCγ), preprodynorphin (ppD), and kappa opioid receptor (KOR), key players in chronic pain mechanisms, was determined in the dorsal spinal cord. Twenty-eight days after injury, all vehicle-treated animals presented allodynic behaviors and a marked increase in NMDAR subunits, PKCγ, and ppD mRNA levels, with no changes in KOR mRNA levels. Progesterone prevented the development of mechanical allodynia and reduced the painful responses to cold stimulation. In correlation with the attenuation of pain behaviors, the steroid prevented NMDAR subunits and PKCγ mRNAs upregulation, did not modify the elevated ppD mRNA levels, but increased KOR expression. In conclusion, progesterone modulates neuropathic pain after spinal cord injury, creating a favorable molecular environment that may decrease spinal nociceptive signaling. ⋯ The present study suggests that progesterone administration could represent an interesting strategy to modulate neuropathic pain circuits after spinal cord injury. Further studies are needed to investigate the potential progesterone receptors involved in these actions.
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Spinally released brain-derived nerve growth factor (BDNF) after nerve injury is essential to anatomic and functional changes in spinal noradrenergic and cholinergic systems, which are engaged or targeted by commonly used treatments for neuropathic pain. Since BDNF signals via tropomyosine receptor kinases (trks), we tested whether trk blockade by repeated spinal injection of the trk inhibitor K252a would reduce anatomical (spinal noradrenergic and cholinergic fiber density), functional (α2-adrenoceptor-mediated direct stimulation of spinal cholinergic terminals), and behavioral (anti-hypersensitivity from systemic gabapentin and spinal clonidine) plasticity, which depends on BDNF. Spinal K252a treatment did not alter hypersensitivity from spinal nerve ligation (SNL), but blocked the SNL-associated increase in dopamine-β-hydroxylase (DβH) fiber density in the spinal cord dorsal horn while reducing spinal choline acetyltransferase (ChAT)-immunoreactivity. K252a treatment also abolished the facilitatory effect of dexmedetomidine on KCl-evoked acetylcholine release in spinal cord synaptosomes and reduced the anti-hypersensitivity effects of oral gabapentin and spinal clonidine. These results suggest that spinal trk signaling is essential for the anatomic and functional plasticity in noradrenergic and cholinergic systems after nerve injury and consequently for the analgesia from drugs that rely on these systems. ⋯ Many drugs approved for neuropathic pain engage spinal noradrenergic and cholinergic systems for analgesia. This study demonstrates that spinal trk signaling after nerve injury is important to neuroplasticity of these systems, which is critical for the analgesic action of common treatments for neuropathic pain.
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The expression of NF-κB in the spinal cord is associated with neuropathic pain. However, little is known about its expression beyond the spinal cord. Here we examined a spatial and temporal pattern of the NF-κB expression in both spinal and supraspinal regions. After chronic constriction injury (CCI) of the sciatic nerve, NF-κB (p65) expression was significantly increased in the ipsilateral spinal cord. In contrast, the NF-κB expression in the contralateral primary somatosensory cortex was decreased with no significant differences seen in the thalamus. In the contralateral anterior cingulate cortex, the NF-κB expression was increased significantly on day 14 as compared with the sham group. In the contralateral amygdala, the NF-κB expression showed a time-dependent downregulation after CCI, which became significant on day 14. MK-801 reduced nociceptive behaviors and reversed the direction of NF-κB expression. These results indicate that the CCI-induced expression of p65 NF-κB is both time-dependent and region-specific, in areas that process both sensory-discriminative and motivational-affective dimensions of pain. ⋯ This article presents a spatiotemporal mapping of the NF-κB expression in spinal and supraspinal regions after peripheral nerve injury. These findings point to an involvement of NF-κB beyond the spinal cord in both the sensory discriminative and emotional affective aspects of neuropathic pain processing.