Pain
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Proteases and protease-activated receptors (PARs) are major mediators involved in irritable bowel syndrome (IBS). Our objectives were to decipher the expression and functionality (calcium signaling) of PARs in human dorsal root ganglia (DRG) neurons and to define mechanisms involved in human sensory neuron signaling by IBS patient mediators. Human thoracic DRG were obtained from the national disease resource interchange. ⋯ Thrombin increased calcium flux, which was inhibited by a PAR1 antagonist and increased by a PAR4 antagonist. Supernatants from colonic biopsies of patients with IBS induced calcium flux in human sensory neurons compared with healthy controls, and this induction was reversed by a PAR1 antagonist. Taken together, our results highlight that PAR1 antagonism should be investigated as a new therapeutic target for IBS symptoms.
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Quantitative sensory testing after macroreplantation: evidence for a specific somatosensory profile.
A comprehensive functional recovery is one of the criteria for successful replantation of an amputated limb. Functionality of a replanted limb is strongly dependent on its regained sensibility. In previous studies concerning the sensibility of replanted limbs, only a few somatosensory submodalities were examined in small samples. ⋯ This distinct profile of impaired somatosensation shares some features of the somatosensory profile of neuropathic pain syndromes. Patients' limbs that were replanted many years before the present quantitative sensory testing showed more sensory deficits than patients with more recent replantations. This knowledge might be helpful in the development of more specific and more successful rehabilitation programs with replanted patients and improves the behavioral function of the replanted limb.
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Heat pain and its modulation by capsaicin varies among subjects in experimental and clinical settings. A plausible cause is a genetic component, of which TRPV1 ion channels, by their response to both heat and capsaicin, are primary candidates. However, TRPA1 channels can heterodimerize with TRPV1 channels and carry genetic variants reported to modulate heat pain sensitivity. ⋯ Of note, TRPA1 variants were more important for correct phenotype group association than TRPV1 variants. This indicates a role of the TRPA1 and TRPV1 next-generation sequencing-based genetic pattern in the modulation of the individual response to heat-related pain phenotypes. When considering earlier evidence that topical capsaicin can induce neuropathy-like quantitative sensory testing patterns in healthy subjects, implications for future analgesic treatments with transient receptor potential inhibitors arise.
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Comparative Study
Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research.
Molecular neurobiological insight into human nervous tissues is needed to generate next-generation therapeutics for neurological disorders such as chronic pain. We obtained human dorsal root ganglia (hDRG) samples from organ donors and performed RNA-sequencing (RNA-seq) to study the hDRG transcriptional landscape, systematically comparing it with publicly available data from a variety of human and orthologous mouse tissues, including mouse DRG (mDRG). We characterized the hDRG transcriptional profile in terms of tissue-restricted gene coexpression patterns and putative transcriptional regulators, and formulated an information-theoretic framework to quantify DRG enrichment. ⋯ Comparison of hDRG and tibial nerve transcriptomes suggests trafficking of neuronal mRNA to axons in adult hDRG, and are consistent with studies of axonal transport in rodent sensory neurons. We present our work as an online, searchable repository (https://www.utdallas.edu/bbs/painneurosciencelab/sensoryomics/drgtxome), creating a valuable resource for the community. Our analyses provide insight into DRG biology for guiding development of novel therapeutics and a blueprint for cross-species transcriptomic analyses.
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Activation of innate immune mechanisms within the dorsal root ganglion and spinal dorsal horn has been shown to play a key role in the development of neuropathic pain including paclitaxel-related chemotherapy-induced peripheral neuropathy (CIPN). Here, we tested whether similar mechanisms are generalizable to oxaliplatin-induced CIPN. After a single intraperitoneal injection of 3 mg/kg oxaliplatin, mechanical withdrawal threshold and the expression of C-C chemokine ligand 2 (CCL2) and its receptor, CCR2, in the dorsal root ganglion were measured by behavioral testing and immunohistochemical staining, respectively. ⋯ Cotreatment with intrathecal anti-CCL2 antibodies prevented the development of oxaliplatin-induced mechanical hyperresponsiveness, and transiently reversed established hyperalgesia when given 1 week after chemotherapy. This is the first study to demonstrate CCL2/CCR2 signaling in a model of oxaliplatin-related CIPN; and it further shows that blocking of this signal can attenuate the development of oxaliplatin-induced mechanical hyperalgesia. Activation of innate immune mechanisms may therefore be a generalized basis for CIPN irrespective of the specific class of agent.