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Large amino acid transporter 1 (LAT1), also known as SLC7A5, is an essential amino acid transporter that forms a heterodimeric complex with the glycoprotein cell-surface antigen heavy chain (4F2hc (CD98, SLC3A2)). Within nociceptive pathways, LAT1 is expressed in the dorsal root ganglia and spinal cord. Although LAT1 expression is upregulated following spinal cord injury, little is known about LAT1 in neuropathic pain. To date, only circumstantial evidence supports LAT1/4F2hc's role in pain. Notably, LAT1's expression and regulation link it to key cell types and pathways implicated in pain. Transcriptional regulation of LAT1 expression occurs via the Wnt/frizzled/β-catenin signal transduction pathway, which has been shown to be involved in chronic pain. The LAT1/4F2hc complex may also be involved in pain pathways related to T- and B-cells. LAT1's expression induces activation of the mammalian target of rapamycin (mTOR) signaling axis, which is involved in inflammation and neuropathic pain. Similarly, hypoxia and cancer induce activation of hypoxia-inducible factor 2 alpha, promoting not only LAT1's expression but also mTORC1's activation. Perhaps the strongest evidence linking LAT1 to pain is its interactions with key voltage-gated ion channels connected to nociception, namely the voltage-gated potassium channels Kv1.1 and Kv1.2 and the voltage-gated sodium channel Nav1.7. Through functional regulation of these channels, LAT1 may play a role in governing the excitatory to inhibitory ratio which is altered in chronic neuropathic pain states. Remarkably, the most direct role for LAT1 in pain is to mediate the influx of gabapentin and pregabalin, two first-line neuropathic pain drugs, that indirectly inhibit high voltage-activated calcium channel auxiliary subunit α2δ-1. In this review, we discuss the expression, regulation, relevant signaling pathways, and protein interactions of LAT1 that may link it to the development and/or maintenance of pain. We hypothesize that LAT1 expressed in nociceptive pathways may be a viable new target in pain.
Learn More >Transient receptor potential ankyrin 1 (TRPA1) is well documented as an important molecule in pain hypersensitivity following inflammation and nerve injury and in many other cellular biological processes. Here, we show that TRPA1 is expressed not only by sensory neurons of the dorsal root ganglia (DRG) but also in their adjacent satellite glial cells (SGCs), as well as nonmyelinating Schwann cells. TRPA1 immunoreactivity is also detected in various cutaneous structures of sensory neuronal terminals, including small and large caliber cutaneous sensory fibers and endings. The SGC-expressed TRPA1 is functional. Like DRG neurons, dissociated SGCs exhibit a robust response to the TRPA1-selective agonist allyl isothiocyanate (AITC) by an increase of intracellular Ca concentration ([Ca]). These responses are abolished by the TRPA1 antagonist HC030031 and are absent in SGCs and neurons from global TRPA1 null mice. SGCs and neurons harvested from DRG proximal to painful tissue inflammation induced by plantar injection of complete Freund's adjuvant show greater AITC-evoked elevation of [Ca] and slower recovery compared to sham controls. Similar TRPA1 sensitization occurs in both SGCs and neurons during neuropathic pain induced by spared nerve injury. Together, these results show that functional TRPA1 is expressed by sensory ganglia SGCs, and TRPA1 function in SGCs is enhanced after both peripheral inflammation and nerve injury, and suggest that TRPA1 in SGCs may contribute to inflammatory and neuropathic pain.
Learn More >To evaluate the patterns of treatment among patients with fibromyalgia (FM) in Spain and to assess patient satisfaction and perceived tolerability of the treatment received.
Learn More >High frequency spontaneous activity in injured primary afferents has been proposed as a pathological mechanism of neuropathic pain following nerve injury. Although spinal infusion of glial cell line-derived neurotrophic factor (GDNF) reduces the activity of injured myelinated A-fiber neurons after 5th lumbar (L5) spinal nerve ligation (SNL) in rats, the implicated molecular mechanism remains undetermined. The fast-inactivating transient A-type potassium current (IA) is an important determinant of neuronal excitability, and five voltage-gated potassium channel (Kv) alpha-subunits, Kv1.4, Kv3.4, Kv4.1, Kv4.2, and Kv4.3, display IA in heterologous expression systems. Here, we examined the effect of spinal GDNF infusion on IA and the expression of these five Kv mRNAs in injured A-fiber neurons using the in vitro patch clamp technique and in situ hybridization histochemistry. GDNF infusion reversed axotomy-induced reduction of the rheobase, elongation of first spike duration, and depolarization of the resting membrane potential. L5 SNL significantly reduced the current density of IA and GDNF treatment reversed the reduction. Among the examined Kv mRNAs, only the change in Kv4.1-expression was parallel with the change in IA after SNL and GDNF treatment. These findings suggest that GDNF should reduce the hyperexcitability of injured A-fiber primary afferents by IA recurrence. Among the five IA-related Kv channels, Kv4.1 should be a key channel, which account for this IA recurrence.
Learn More >Migraine is triggered by poor air quality and odors through unknown mechanisms. Activation of the trigeminovascular pathway by environmental irritants may occur via activation of TRPA1 receptors on nasal trigeminal neurons, but how that results in peripheral and central sensitization is unclear. The anatomy of the trigeminal ganglion suggests that noxious nasal stimuli are not being transduced to the meninges by axon reflex but likely through intraganglionic transmission. Consistent with this concept, we injected CGRP, ATP or glutamate receptor antagonists or a gap junction channel blocker directly and exclusively into the trigeminal ganglion and blocked meningeal blood flow changes in response to acute nasal TRP agonists. Previously, we observed chronic sensitization of the trigeminovascular pathway after acrolein exposure, a known TRPA1 receptor agonist. To explore the mechanism of this sensitization, we utilized laser dissection microscopy to separately harvest nasal and meningeal trigeminal neuron populations in the absence or presence of acrolein exposure. mRNA levels of neurotransmitters important in migraine were then determined by RT-PCR. TRPA1 message levels were significantly increased in meningeal cell populations following acrolein exposure compared to room air exposure. This was specific to TRPA1 message in meningeal cell populations as changes were not observed in either nasal trigeminal cell populations or dorsal root ganglion populations. Taken together, this data suggests an important role for intraganglionic transmission in acute activation of the trigeminovascular pathway. It also supports a role for upregulation of TRPA1 receptors in peripheral sensitization and a possible mechanism for chronification of migraine after environmental irritant exposure.
Learn More >Use of prescription opioids and problems of abuse and addiction have increased over the past decade. Claims-based studies have documented substantial economic burden of opioid abuse. This study utilized electronic health record (EHR) data to identify chronic opioid therapy (COT) patients with problem opioid use (POU) and compared costs with those for COT patients without POU. This study utilized EHR and claims data from an integrated health care system. Patients received COT (≥70 days' supply in ≥1 calendar quarter, 2006-2012). Natural language processing (NLP) identified notations of opioid addiction, abuse, misuse, or overuse, and manual validation was performed. Cases had evidence of POU (index = first POU notation), and controls, sampled 9:1, did not. Health care resource utilization was measured and costs estimated using Medicare reimbursement rates. A longitudinal analysis of costs was conducted using generalized estimating equations. Adjusted analyses controlled for baseline age, gender, region, specific comorbidities, and a comorbidity index. The analysis population included 1,125 cases and 10,128 controls. Unadjusted costs were higher for cases in all three years. After controlling for covariates, total costs remained higher in cases and were significantly higher in the first year of follow-up ($38,064 vs. $31,674, P = .0048). The largest cost difference was observed in the first month of follow-up. COT patients with POU experienced significantly higher costs compared with COT patients without POU in the first year of follow-up. The greatest difference in costs was observed around identification of POU.
Learn More >Sensitivity to different pain modalities has a genetic basis that remains largely unknown. Employing closely related inbred mouse substrains can facilitate gene mapping of nociceptive behaviors in preclinical pain models. We previously reported enhanced sensitivity to acute thermal nociception in C57BL/6J (B6J) versus C57BL/6N (B6N) substrains. Here, we expanded on nociceptive phenotypes and observed an increase in formalin-induced inflammatory nociceptive behaviors and paw diameter in B6J versus B6N mice (Charles River Laboratories). No strain differences were observed in mechanical or thermal hypersensitivity or in edema following the Complete Freund's Adjuvant (CFA) model of inflammatory pain, indicating specificity in the inflammatory nociceptive stimulus. In the chronic nerve constriction injury (CCI), a model of neuropathic pain, no strain differences were observed in baseline mechanical threshold or in mechanical hypersensitivity up to one month post-CCI. We replicated the enhanced thermal nociception in the 52.5°C hot plate test in B6J versus B6N mice from The Jackson Laboratory. Using a B6J x B6N-F2 cross (N=164), we mapped a major quantitative trait locus (QTL) underlying hot plate sensitivity to chromosome 7 that peaked at 26 Mb (LOD=3.81, p<0.01; 8.74 Mb-36.50 Mb) that was more pronounced in males. Genes containing expression QTLs (eQTLs) associated with the peak nociceptive marker that are implicated in pain and inflammation include Ryr1, Cyp2a5, Pou2f2, Clip3, Sirt2, Actn4, and Ltbp4 (FDR < 0.05). Future studies involving positional cloning and gene editing will determine the quantitative trait gene(s) and potential pleiotropy of this locus across pain modalities.
Learn More >The incidence of bortezomib-induced neuropathic pain hampers the progress of therapy for neoplasia, and also negatively affects the quality of life of patients. However, the molecular mechanism underlying bortezomib-induced neuropathic pain remains unknown. In the present study, we found that the application of bortezomib significantly increased the expression of GATA binding protein 3 (GATA3) in the spinal dorsal horn, and intrathecal administration of GATA3 siRNA attenuated mechanical allodynia. Furthermore, ChIP-sequencing showed that bortezomib treatment induced the redistribution of GATA3 to transcriptional relevant regions. Notably, combined with the results of mRNA microarray, we found that C-C motif chemokine ligand 21 (CCL21) had an increased GATA3 binding and upregulated mRNA expression in the dorsal horn after bortezomib treatment. Next, we found that bortezomib treatment induced CCL21 upregulation in the spinal neurons, which was significantly reduced upon GATA3 silencing. Blockade of CCL21 using the neutralizing antibody or special siRNA ameliorated mechanical allodynia induced by bortezomib. In addition, bortezomib treatment increased the acetylation of histone H3 and the interaction between GATA3 and CREB-binding protein (CBP). GATA3 siRNA suppressed the CCL21 upregulation by decreasing the acetylation of histone H3. Together, these results suggested that activation of GATA3 mediated the epigenetic upregulation of CCL21 in dorsal horn neurons, which contributed to the bortezomib-induced neuropathic pain.
Learn More >The present study examined how multiple chronic pain conditions and pain sites are associated with socio-demographics, chronic pain adjustment profiles, and emotional distress. A total of 2407 individuals who reported at least six months of having consistent pain severity, pain interference, and/or emotional burden due to pain were recruited through random digit dialing across the United States. Participants' chronic pain adjustment profiles (i.e., pain intensity, pain interference, emotional burden, pain catastrophizing, pain coping, pain attitudes, and social resources) were assessed. Anxiety and depressive symptoms were also measured using a subsample of 181 participants who provided three-month follow-up data. More than 60% of individuals with chronic pain reported having multiple pain conditions. Middle-aged single women with fibromyalgia, disability and of low socioeconomic status reported a greater number of pain conditions and pain sites. Structural equation modeling revealed that a higher number of pain conditions and sites was associated with more dysfunctional chronic pain adjustment profiles. The subsample analyses showed that reporting a greater number of pain conditions predicted a higher level of depression and anxiety three months later, controlling for pain-related anxiety and depressive symptoms, pain severity and interference at baseline. Having multiple pain conditions and sites may represent a psychosocial barrier to successful adjustment to chronic pain. Perspectives: This article argues for the importance of assessing the number of co-occurring chronic pain conditions and bodily areas that are affected by pain in both pain research and clinical settings. Measuring and incorporating such information could potentially enhance our nascent understanding of the adjustment processes of chronic pain.
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