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Sensitisation of colonic nociceptors by TNFα is dependent on TNFR1 expression and p38 MAPK activity.
The pro-inflammatory cytokine TNFα is elevated in GI disease and sensitises colonic afferents via modulation of TRPA1 and Na 1.8 activity. We further develop this understanding by demonstrating a role for p38 MAPK and TRPV1 in TNFα mediated colonic afferent sensitisation. Specifically, we show that: TNFα sensitises sensory neurons and colonic afferents to the TRPV1 agonist capsaicin. TNFα-mediated sensitisation of sensory neurons and colonic nociceptors is dependent on TNFR1 expression. TNFα sensitisation of sensory neurons and colonic afferents to capsaicin and noxious ramp distension is abolished by inhibition of p38 MAPK. Collectively this data supports the utility of targeting TNFα, TNFR1 and their downstream signalling via p38 MAPK for the treatment of visceral pain in GI disease.
Learn More >Neuropathic pain is refractory to opioid analgesics. Since there are functional linkages between μ-opioid receptors (MOR) and cannabinoid receptors (CBR), the present study was designed to investigate the interactions between MOR and CBR based on antinociceptive effects for neuropathic pain mediated through G protein-coupled inwardly-rectifying potassium channels (GIRKs). The antinociceptive effects against pseudonociceptive response or neuropathic pain of MOR and CBR agonists were assessed in mice with or without partial sciatic nerve ligation. To investigate the functional interaction between MOR and CBR, electrophysiological recording through GIRK was performed using the two-electrode voltage-clamp method in oocytes along with Western blotting in the spinal cord of mice. Co-administration of the MOR agonist DAMGO and the CBR agonist CP55,940 augmented inwardly rectifying K currents in Xenopus oocytes co-expressing MOR, CBR and GIRK1/2. Further, combination of morphine and the CBR agonist WIN-55,212-2 produced prominent antinociceptive effects in an i.t. GIRK1 inhibitor-reversible manner. Furthermore, CBR was upregulated under neuropathic pain in the spinal cord, and such upregulation and antinociceptive effects were not altered by repeated treatment with morphine plus WIN-55,212-2. Our findings suggest that co-administration of MOR and CBR agonists could enhance their antinociceptive effects through GIRK1 in the spinal cord of mice.
Learn More >Spinal cord stimulation (SCS) is increasingly utilized in the treatment of multiple chronic pain conditions. However, patients will continue to experience other medical issues and the potential for future magnetic resonance imaging (MRI) needs must not be overlooked. SCS devices have device-specific MRI conditional labeling and if impedances are elevated the patient may not be able to obtain an MRI. With 10 kHz SCS devices specifically, an impedance value above 10,000 ohms (Ω) is MRI ineligible. The primary objective of this article was to report the incidence of elevated impedances with a multilumen lead design per electrode, per lead, and to describe the total number of MRI ineligible patients due to elevated impedances using 10 kHz SCS cutoff values. The secondary objective was to determine whether certain patient demographics or surgery characteristics put patients at increased risk of elevated impedances.
Learn More >Maladaptive changes of nerve injury-associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury-specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury-induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury-induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.
Learn More >Since new roles of nucleotides as neurotransmitters were proposed by Geoffrey Burnstock, the roles of ATP and P2 receptors (P2Rs) have been extensively studied in pain signaling. This review primarily focuses on the history and roles of P2X2Rs and P2X2/3Rs in acute and chronic pain, and P2X4Rs in neuropathic pain after peripheral nerve injury (PNI). Spinal microglial activity mediated by P2X4Rs shows a very important contribution to evoking neuropathic pain, and P2X4Rs might be targets for the treatment of neuropathic pain. The advantage of P2X4Rs of microglia as therapeutic targets is that P2X4Rs are predominantly enhanced in activated microglia after PNI, and P2X4R blockers do not affect normal pain signaling. Currently, many excellent P2R-related drug candidates are being developed, and it seems that the day when we will use them in clinical practice is not too far away.
Learn More >Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges.
Learn More >Trigeminal neuropathic pain (TNP) arises due to peripheral nerve injury, the mechanisms underlying which are little known. The altered gene expression profile in sensory ganglia is critical for neuropathic pain generation and maintenance. We, therefore, assessed the transcriptome of the trigeminal ganglion (TG) from mice at different periods of pain progression. Trigeminal neuropathic pain was established by partial infraorbital nerve transection (pIONT). High-throughput RNA sequencing was applied to detect the mRNA profiles of TG collected at 3 and 10 days after modeling. Injured TG displayed dramatically altered mRNA expression profiles compared to Sham. Different gene expression profiles were obtained at 3 and 10 days after pIONT. Moreover, 314 genes were significantly upregulated, and 81 were significantly downregulated at both 3 and 10 days post-pIONT. Meanwhile, enrichment analysis of these persistent differentially expressed genes (DEGs) showed that the MAPK pathway was the most significantly enriched pathway for upregulated DEGs, validated by immunostaining. In addition, TG cell populations defined by single-nuclei RNA sequencing displayed cellular localization of DEGs at a single-cell resolution. Protein-protein interaction (PPI) and sub-PPI network analyses constructed networks and identified the top 10 hub genes for DEGs at different time points. The present data provide novel information on the gene expression signatures of TG during the development and maintenance phases of TNP, and the identified hub genes and pathways may serve as potential targets for treatment.
Learn More >With symptoms such as spontaneous pain and pathologically heightened sensitivity to stimuli, chronic pain accounts for about 20% of physician visits and up to 2/3 of patients are dissatisfied with current treatments. Much of our knowledge on pain processing and analgesics has emerged from behavioral studies performed on animals presenting the same symptoms under pathological conditions. While humans can verbally describe their pain, studies on rodents have relied on behavioral assays providing non-exhaustive characterization or altering animals' original sensitivity through repetitive stimulations. The emergence of what we term "next-generation behavioral sequencing" is now permitting us to quantitatively describe behavioral features on millisecond to minutes long timescales that lie beyond easy detection with the unaided eye. Here, we summarize emerging videography and computational based behavioral approaches that have the potential to significantly improve pain research.
Learn More >Lack of clarity regarding effective communication behaviors in chronic pain management is a barrier for implementing psychologically informed physical therapy approaches that rely on competent communication by physical therapist providers. This study aimed to conduct a systematic review and meta-synthesis to inform the development of a conceptual framework for preferred communication behaviors in pain rehabilitation.
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