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Almost 17 million Americans have a history of cancer, a number expected to reach over 22 million by 2030. Cancer patients often undergo chemotherapy in the form of antineoplastic agents such as -platin and paclitaxel. Though effective, these agents can induce debilitating side effects; the most common neurotoxic effect, chemotherapy-induced peripheral neuropathy (CIPN), can endure long after treatment ends. Despite the widespread and chronic nature of the dysfunction, no tools exist to quantitatively measure chemotherapy-induced peripheral neuropathy. Such a tool would not only benefit patients but their stratification could also save significant financial and social costs associated with neuropathic pain. In our first step toward addressing this unmet clinical need, we explored a novel dual approach to localize peripheral nerves: Cerenkov luminescence imaging (CLI) and fluorescence imaging (FI). Our approach revolves around the targeting and imaging of voltage-gated sodium channel subtype Na1.7, highly expressed in peripheral nerves from both harvested human and mouse tissues. For the first time, we show that Hsp1a, a radiolabeled Na1.7-selective peptide isolated from spec. Peru, can serve as a targeted vector for delivering a radioactive sensor to the peripheral nervous system. , we observe high signal-to-noise ratios in the sciatic nerves of animals injected with fluorescently labeled Hsp1a and radiolabeled Hsp1a. Moreover, confocal microscopy on fresh nerve tissue shows the same high ratios of fluorescence, corroborating our results. This study indicates that fluorescently labeled and radiolabeled Hsp1a tracers could be used to identify and demarcate nerves in a clinical setting.
Learn More >Spinal inflammation is a pathophysiological state of neuropathic pain (NP). The subsequent microglial activation and neuroinflammatory response are contributing factors for long-lasting behavioral hypersensitivity. Valproic acid (VPA), a histone deacetylase inhibitor, has promising anti-inflammatory and neuroprotective properties for clinical use in the treatment of neurological disorders. However, the underlying mechanisms of its effects on NP have not been determined. This study aimed to clarify the possible mechanisms by which VPA alleviates NP in rat models induced by spinal nerve ligation (SNL). Intraperitoneal injection of VPA (300 mg/kg) efficiently attenuated mechanical allodynia in rats with NP. VPA exerted anti-inflammatory effects by downregulating proinflammatory cytokines (tumor necrosis factor-α, cytokines interleukin-1β, cytokines interleukin-6; TNF-α, IL-1β, and IL-6) and upregulating anti-inflammatory cytokines (transforming growth factor-β, cytokines interleukin-10, cytokines interleukin-4; TGF-β, IL-10 and IL-4). Additionally, VPA suppressed spinal microgliosis and promoted the polarization of microglia towards the M2 phenotype to further ameliorate spinal neuroinflammation. VPA also exerted neuroprotective effects by decreasing spinal cell apoptosis. The anti-inflammatory and neuroprotective effects may have depended on changes in nuclear histone deacetylase 3 (HDAC3) expression following VPA treatment. Moreover, VPA treatment inhibited nuclear factor-κB (NF-κB) p65 nuclear expression and upregulated acetylated the signal transducer and activator of transcription 1 (STAT1). In addition, VPA suppressed SNL-induced phosphorylation of Janus Kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3). Taken together, our results demonstrate that VPA is a promising anti-inflammatory agent suitable for NP therapy that regulates microglial function and suppresses spinal neuroinflammation via the STAT1/NF-κB and JAK2/STAT3 signaling pathways.
Learn More >Pain puts patients at risk for developing psychiatric conditions such as anxiety and depression. Pre-clinical mouse models of pain-induced affective behavior vary widely in methodology and results, impairing progress towards improved therapeutics. To systematically investigate the effect of long-term inflammatory pain on exploratory behavior and stress coping strategy, we assessed male C57BL/6J mice in the forced swim test (FST), elevated zero maze (EZM), and open field test (OFT) at four and six weeks post-injection of Complete Freund's Adjuvant (CFA), while controlling for testing order and combination. Inflammatory pain did not induce a passive stress coping strategy in the FST and did not reduce exploratory behavior in the EZM or the OFT. Using systematic correlational analysis and composite behavioral scores, we found no consistent association among measures for mice with or without inflammatory pain. A meta-analysis of similar studies indicated a modest, significant effect of CFA on exploratory behavior, but not immobility in the FST, and high heterogeneity among effect sizes in all three paradigms. Given the urgency for understanding the mechanisms of pain comorbidities and identifying novel therapies, these findings support the reallocation of our limited resources away from such unreliable assays and toward motivated and naturalistic behaviors. Future studies in pain and psychiatric translational research may benefit by considering outcomes beyond binary categorization, quantifying the associations between multiple measured behaviors, and agnostically identifying subtle yet meaningful patterns in behaviors.
Learn More >Adults are more likely to suffer from chronic pain than minors, and its underlying mechanism remains unclear. SIRT1 as important aging-related protein with function of lifespan extension, whether SIRT1 plays a role in the different pain vulnerability of adult and juvenile remains unclear. Here, we found that the expression level of SIRT1 in dorsal root ganglia (DRG) was related to the pain vulnerability. Following nerve injury, the expression of SIRT1 in DRG was decreased in adult rodents while increased in juvenile rodents. Differential manipulation of SIRT1 abolished the different pain vulnerability between adult and juvenile rodents. Furthermore, SIRT1 interacted with ClC-3 channel and mediated ClC-3 membrane trafficking and Cl¯ current in DRG neurons. Differential manipulation of ClC-3 also abolished the difference in pain vulnerability between adult and juvenile rodents. The different anti-inflammatory ability determined the different change trends of SIRT1 and ClC-3 trafficking contributed to the different pain vulnerability in adult and juvenile rodents. In addition, the serum SIRT1 level was negatively correlated with pain score in chronic pain patients. These findings revealed the mechanism of the difference in pain vulnerability between adult and juvenile rodents and provided evidence for age-specific treatment of chronic pain.
Learn More >Central sensitization is an important pathophysiological mechanism of chronic migraine (CM). According to our previous studies, microglial activation and subsequent inflammation in the trigeminal nucleus caudalis (TNC) contribute to the central sensitization. The P2X7 receptor (P2X7R) is a purinergic receptor expressed in microglia and participates in central sensitization in chronic pain, but its role in CM is unclear. Numerous studies have shown that P2X7R regulates the level of autophagy and that autophagy affects the microglial activation and inflammation. Recently, autophagy has been shown to be involved in neuropathic pain, but there is no information about autophagy in CM. Therefore, the current study investigated the role of P2X7R in CM and its underlying mechanism, focusing on autophagy regulation.
Learn More >Old age and female sex are risk factors for the development of osteoarthritis (OA) and chronic pain. We investigated the effects of sex and age on pain modulatory networks in a healthy state and during OA progression. We used functional MRI to determine the effects of sex and age on periaqueductal gray functional connectivity (PAG FC) in a healthy state (pre-OA) and during the early and late phases of monosodium iodoacetate-induced OA in rats. We then examined how sex and age affect longitudinal changes in PAG FC in OA. In a healthy state, females exhibited more widespread PAG FC than males, and this effect was exaggerated with aging. Young males had moderate PAG FC changes during the early phase but recruited additional brain regions, including the rostral anterior cingulate cortex (ACC), during the late phase. Young females exhibited widespread PAG FC in the early phase, which includes connections to insula, caudal ACC, and nucleus accumbens (NAc). Older groups had strong PAG FC with fewer regions in the early phase, but they recruited additional brain regions, including NAc, in the late phase. Overall, our findings show that PAG FC is modulated by sex and age in a healthy state. A widespread PAG network in the early phase of OA pain may contribute to the transition from acute to chronic OA pain and the increased risk of developing chronic pain for females. Enhanced PAG FC with the reward system may represent a potential mechanism underlying chronic OA pain in elderly patients.
Learn More >Early-life stress (ELS) is a high-risk factor for the development of chronic visceral pain in adulthood. Emerging evidence suggests that mast cells play a key role in the development of visceral hypersensitivity through interaction with neurons. The sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the pathogenesis of visceral pain. However, the precise mechanism by which mast cells and CRF neurons interact in the PVN in the pathogenesis of visceral hypersensitivity remains elusive. In the present study, we used neonatal maternal separation (MS), an ELS model, and observed that neonatal MS induced visceral hypersensitivity and triggered PVN mast cell activation in adult rats, which was repressed by intra-PVN infusion of the mast cell stabilizer disodium cromoglycate (cromolyn). Wild-type (WT) mice but not mast cell-deficient Kit mice that had experienced neonatal MS exhibited chronic visceral hypersensitivity. MS was associated with an increase in the expression of proinflammatory mediators, the number of CRF cells and CRF protein in the PVN, which was prevented by intra-PVN infusion of cromolyn. Furthermore, we demonstrated that intra-PVN infusion of the mast degranulator compound 48/80 significantly induced mast cell activation, resulting in proinflammatory mediator release, CRF neuronal sensitization, and visceral hypersensitivity, which was suppressed by cromolyn. Overall, our findings demonstrated that neonatal MS induces the activation of PVN mast cells, which secrete numerous proinflammatory mediators that may participate in neighboring CRF neuronal activity, ultimately directly inducing visceral hypersensitivity in adulthood.
Learn More >Sickle cell disease (SCD) is a common hereditary hematologic disorder. SCD patients suffer from acute vaso-occlusive episodes (VOEs), chronic organ damage, and premature death, with few therapeutic options. Although severe pain is a major clinical manifestation of SCD, it remains unknown whether nociception plays a role in SCD pathogenesis. To address this question, we generated nociceptor-deficient SCD mice and found, unexpectedly, that the absence of nociception led to more severe and more lethal VOE, indicating that somatosensory nerves protect SCD mice from VOE. Mechanistically, the beneficial effects of sensory nerves were induced by the neuropeptide calcitonin gene-related peptide (CGRP), which acted on hematopoietic cells. Additionally, oral capsaicin consumption, which can activate somatosensory nerves by binding to TRPV1, dramatically alleviated acute VOE and significantly prevented chronic liver and kidney damage in SCD mice. Thus, the manipulation of nociception may provide a promising approach to treat SCD.
Learn More >Earlier studies show that endogenous sphingolipids can induce pain hypersensitivity, activation of spinal astrocytes, release of proinflammatory cytokines and activation of TRPM3 channel. Here we studied whether the development of pain hypersensitivity induced by sphingolipids in the spinal cord can be prevented by pharmacological inhibition of potential downstream mechanisms that we hypothesized to include TRPM3, σ and NMDA receptors, gap junctions and D-amino acid oxidase.
Learn More >Functional Coupling of Slack Channels and P2X3 Receptors Contributes to Neuropathic Pain Processing.
The sodium-activated potassium channel Slack (K1.1, Slo2.2, or Kcnt1) is highly expressed in populations of sensory neurons, where it mediates the sodium-activated potassium current (I) and modulates neuronal activity. Previous studies suggest that Slack is involved in the processing of neuropathic pain. However, mechanisms underlying the regulation of Slack activity in this context are poorly understood. Using whole-cell patch-clamp recordings we found that Slack-mediated I in sensory neurons of mice is reduced after peripheral nerve injury, thereby contributing to neuropathic pain hypersensitivity. Interestingly, Slack is closely associated with ATP-sensitive P2X3 receptors in a population of sensory neurons. In vitro experiments revealed that Slack-mediated I may be bidirectionally modulated in response to P2X3 activation. Moreover, mice lacking Slack show altered nocifensive responses to P2X3 stimulation. Our study identifies P2X3/Slack signaling as a mechanism contributing to hypersensitivity after peripheral nerve injury and proposes a potential novel strategy for treatment of neuropathic pain.
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