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The Sigma-1 receptor (σR) is highly expressed in the primary sensory neurons (PSNs) that are the critical site of initiation and maintenance of pain following peripheral nerve injury. By immunoblot and immunohistochemistry, we observed increased expression of both σR and σR-binding immunoglobulin protein (BiP) in the lumbar (L) dorsal root ganglia (DRG) ipsilateral to painful neuropathy induced by spared nerve injury (SNI). To evaluate the therapeutic potential of PSN-targeted σR inhibition at a selected segmental level, we designed a recombinant adeno-associated viral (AAV) vector expressing a small hairpin RNA (shRNA) against rat σR. Injection of this vector into the L4/L5 DRGs induced downregulation of σR in DRG neurons of all size groups, while expression of BiP was not affected. This was accompanied by attenuation of SNI-induced cutaneous mechanical and thermal hypersensitivity. Whole-cell current-clamp recordings of dissociated neurons showed that knockdown of σR suppressed neuronal excitability, suggesting that σR silencing attenuates pain by reversal of injury-induced neuronal hyperexcitability. These findings support a critical role of σR in modulating PSN nociceptive functions, and that the nerve injury-induced elevated σR activity in the PSNs can be a significant driver of neuropathic pain. Further understanding the role of PSN-σR in pain pathology may open routes to exploit this system for DRG-targeted pain therapy.
Prospective trials of enhanced recovery after spine surgery are lacking. We tested the hypothesis that an enhanced recovery pathway improves quality of recovery after one- to two-level lumbar fusion.
Cervical dystonia is the most common form of focal idiopathic dystonia and is frequently associated with pain. Headaches are not considered to be more prevalent amongst patients presenting with cervical dystonia, and headaches attributed to craniocervical dystonia are considered to be a rare disorder, despite the lack of studies and clinical information regarding the subject.
OnabotulinumtoxinA is an effective preventive treatment for chronic migraine. In chronic migraine, besides a reduction in headache frequency, a decreased reliance on oral prophylactics is also indicative of treatment effectiveness. This study aimed to quantify the change in the use of oral prophylactics after treatment with onabotulinumtoxinA in patients with chronic migraine.
Ethnic differences in placebo and nocebo responses are an important, yet underresearched, patient factor that might contribute to treatment disparities.
Central post-stroke pain (CPSP) can arise after lesions anywhere in the central somatosensory pathways, essentially within the spinothalamic system (STS). Although the STS can be selectively injured in the mesencephalon, CPSP has not been described in pure midbrain infarcts.
Rheumatoid arthritis (RA) is an autoimmune disorder. It causes inflammation, swelling, and pain in the joints of the human body. Overexpressed matrix metalloproteinases (MMPs) at the inflammatory sites of RA are a target in the construction of inflammation-responsive drug delivery vehicles for enhancing the therapeutic effect of anti-inflammatory drugs in the treatment of RA. In this paper, we report MMP-responsive PEGylated lipid nanoparticles through the co-assembly of triglycerol monostearate (TGMS) and 1,2-distearoyl–glycero-3-phospho-ethanolamine-poly(ethyleneglycol) (DSPE-PEG) in which the ester bond of TGMS is cleavable by MMPs and the PEG chain provides a stealth layer. The lipid nanoparticles show high biocompatibility, extended blood circulation, and preferential distribution in the inflammatory joints of RA. The loaded dexamethasone (Dex) can be rapidly released from the lipid nanoparticles in response to MMPs. After being intravenously administered to arthritic rats, Dex-loaded MMP-responsive PEGylated lipid nanoparticles significantly reduce the degree of joint swelling and inhibit the production of TNF-α and IL-1β in joint tissues. These results demonstrate that MMP-responsive PEGylated lipid nanoparticles are a smart drug vehicle for the treatment of RA with improved therapeutic efficacy.
Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.
Patients with chronic fatigue syndrome (CFS) and chronic whiplash associated disorders (cWAD) present a reduced ability to activate central descending nociceptive inhibition after exercise, compared to measurements before exercise. It was hypothesised that a dysfunctional motor-induced inhibition of nociception partly explains this dysfunctional exercise-induced hypoalgesia. This study investigates if engagement of the motor system during movement preparation inhibits nociception-evoked brain responses in these patients as compared to healthy controls (HC).
Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow (CT-optimal) and fast (CT-suboptimal) brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula (contralateral to the stimulated arm) during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia.