Pain
-
Racial differences exist in analgesic prescribing for children during emergency department and ambulatory surgery visits in the United States; however, it is unknown whether this is true in the outpatient setting. We examined racial and ethnic differences in outpatient analgesic prescribing using nationally representative data from 113,929 children from the Medical Expenditure Panel Survey. We also examined whether patient-provider race and ethnic concordance was associated with opioid prescription. ⋯ Racial differences exist in analgesic prescriptions to children at outpatient health care visits in the United States, with white children more likely to receive opioids and minorities more likely to receive nonopioid analgesics. Health care providers' race and ethnicity may play a significant role in extant analgesic differences. Further work should focus on understanding the role of provider race and ethnicity in analgesic differences to children in the United States.
-
We previously reported that destruction of the small ubiquitin-like modifier (SUMO) modification site in the axonal collapsin response mediator protein 2 (CRMP2) was sufficient to selectively decrease trafficking of the voltage-gated sodium channel NaV1.7 and reverse neuropathic pain. Here, we further interrogate the biophysical nature of the interaction between CRMP2 and the SUMOylation machinery, and test the hypothesis that a rationally designed CRMP2 SUMOylation motif (CSM) peptide can interrupt E2 SUMO-conjugating enzyme Ubc9-dependent modification of CRMP2 leading to a similar suppression of NaV1.7 currents. Microscale thermophoresis and amplified luminescent proximity homogeneous alpha assay revealed a low micromolar binding affinity between CRMP2 and Ubc9. ⋯ Fluorescence dye-based imaging in rat sensory neurons demonstrated inhibition of sodium influx in the presence of t-CSM peptide; by contrast, calcium influx was unaffected. Finally, t-CSM effectively reversed persistent mechanical and thermal hypersensitivity induced by a spinal nerve injury, a model of neuropathic pain. Structural modeling has now identified a pocket-harboring CRMP2's SUMOylation motif that, when targeted through computational screening of ligands/molecules, is expected to identify small molecules that will biochemically and functionally target CRMP2's SUMOylation to reduce NaV1.7 currents and reverse neuropathic pain.
-
The TRPA1 and TRPV1 receptors are important pharmaceutical targets for antipruritic and analgesic therapy. Obtaining further knowledge on their roles and interrelationship in humans is therefore crucial. Preclinical results are contradictory concerning coexpression and functional interdependency of TRPV1 and TRPA1, but no human evidence exists. ⋯ The capsaicin-ablated skin areas showed significant heat hypoalgesia at baseline (P < 0.001) as well as heat antihyperalgesia, and inhibition of neurogenic inflammation evoked by both 1% capsaicin and 10% AITC provocations (both: P < 0.001). Ablation of cutaneous capsaicin-sensitive afferents caused consistent and equal inhibition of both TRPV1- and TRPA1-provoked responses assessed psychophysically and by imaging of vasomotor responses. This study suggests that TRPA1 nociceptive responses in human skin strongly depend on intact capsaicin-sensitive, TRPV1 fibers.
-
We attempted to gather information on the pathogenesis of medication-overuse headache, as well as on the neurochemical mechanisms through which symptomatic medication overuse concurs to headache chronification. Transcriptional profiles were therefore evaluated as an index of the homeostasis of the trigeminovascular system in the trigeminal ganglion of female rats exposed for 1 month to daily oral doses of eletriptan or indomethacin. We report that both drug treatments change trigeminal ganglion gene expression to a similar extend. ⋯ Of note, lowering of orofacial nociceptive thresholds, as well as forepaw hyperalgesia occurred in both indomethacin- and eletriptan-treated rats. Our study reveals that chronic rat exposure to 2 acute headache medications with completely different mechanisms of action prompts pain sensitization with highly similar induction of pronociceptive genes selectively within the trigeminal ganglion. Data further our understanding of medication-overuse headache pathogenesis and provide hints for specific mechanism-based treatment options.
-
Review
Targeting Toll-like Receptor-4 (TLR4) - Emerging Therapeutic Target for Persistent Pain States.
Toll-like receptors (TLRs) are a family of pattern recognition receptors that initiate signaling in innate and adaptive immune pathways. The highly conserved family of transmembrane proteins comprises an extracellular domain that recognizes exogenous and endogenous danger molecules and an ectodomain that activates downstream pathways in response. Recent studies suggest that continuous activation or dysregulation of TLR signaling may contribute to chronic disease states. ⋯ Procedures blocking TLR functionality have shown pronounced effects on pain behavior otherwise observed in models of chronic inflammation and nerve injury. This review addresses the role of TLR4 as an emerging therapeutic target for the evolution of persistent pain and its role in noncanonical signaling, mediating anomalous pro-algesic actions of opiates. Accordingly, molecules targeting inhibition of this receptor have promise as disease-modifying and opioid-sparing alternatives for persistent pain states.