Accepted

Chronic pain is a common and often debilitating problem that affects 100 million Americans. A better understanding of pain's molecular mechanisms is necessary for developing safe and effective therapeutics. Microglial activation has been implicated as a mediator of chronic pain in numerous preclinical studies; unfortunately, translational efforts using known glial modulators have largely failed, perhaps at least in part due to poor specificity of the compounds pursued, or an incomplete understanding of microglial reactivity. In order to achieve a more granular understanding of the role of microglia in chronic pain as a means of optimizing translational efforts, we utilized a clinically-informed mouse model of complex regional pain syndrome (CRPS), and monitored microglial activation throughout pain progression. We discovered that while both males and females exhibit spinal cord microglial activation as evidenced by increases in Iba1, activation is attenuated and delayed in females. We further evaluated the expression of the newly identified microglia-specific marker, TMEM119, and identified two distinct populations in the spinal cord parenchyma after peripheral injury: TMEM119+ microglia and TMEM119- infiltrating myeloid lineage cells, which are comprised of Ly6G + neutrophils and Ly6G- macrophages/monocytes. Neurons are sensitized by inflammatory mediators released in the CNS after injury; however, the cellular source of these cytokines remains somewhat unclear. Using multiplex hybridization in combination with immunohistochemistry, we demonstrate that spinal cord TMEM119+ microglia are the cellular source of cytokines IL6 and IL1β after peripheral injury. Taken together, these data have important implications for translational studies: 1) microglia remain a viable analgesic target for males and females, so long as duration after injury is considered; 2) the analgesic properties of microglial modulators are likely at least in part related to their suppression of microglial-released cytokines, and 3) a limited number of neutrophils and macrophages/monocytes infiltrate the spinal cord after peripheral injury but have unknown impact on pain persistence or resolution. Further studies to uncover glial-targeted therapeutic interventions will need to consider sex, timing after injury, and the exact target population of interest to have the specificity necessary for translation.

Little is known about the nature of relationships between sleep disturbance and influencing factors in rheumatoid arthritis. The purpose of this study was to identify factors that influence sleep disturbance and to evaluate mediating effects of depression on sleep disturbance. A nonexperimental, descriptive, correlational study design was adopted. One hundred patients with rheumatoid arthritis were recruited. Inflammatory status and levels of pain, fatigue, functional disability, depression, and sleep disturbance were measured. The factors that directly influenced sleep disturbance were gender, rheumatoid arthritis duration, serum C-reactive protein level, fatigue, and depression. Depression was found to have mediating effects on the relationships between sleep disturbance and arthritis symptoms. Pain, fatigue, and depression were found to have significant direct or indirect impacts on sleep disturbance. Our findings may improve understanding of sleep disturbance and aid the development of effective nursing management strategies for patients with rheumatoid arthritis suffering from sleep disturbance.

To perform a scoping review of the literature to elucidate the occurrence of nerve damage related to dental implant placement and the factors causing the sensory changes.

Spinal cord injury (SCI) is a complex syndrome that has profound effects on patient well-being, including the development of medically-resistant chronic pain. The mechanisms underlying SCI pain have been the subject of thorough investigation but remain poorly understood. While the majority of the research has focused on changes occurring within and surrounding the site of injury in the spinal cord, there is now a consensus that alterations within the peripheral nervous system, namely sensitization of nociceptors, contribute to the development and maintenance of chronic SCI pain. Using an skin/nerve/DRG/spinal cord preparation to characterize afferent response properties following SCI, we found that SCI increased mechanical and thermal responding, as well as the incidence of spontaneous activity (SA) and afterdischarge (AD), in below-level C-fiber nociceptors 24 hr following injury relative to naïve controls. Interestingly, the distribution of nociceptors that exhibit SA and AD are not identical, and the development of SA was observed more frequently in nociceptors with low heat thresholds, while AD was found more frequently in nociceptors with high heat thresholds. We also found that SCI resulted in hindpaw edema and elevated cutaneous calcitonin gene-related peptide (CGRP) concentration that were not observed in naïve mice. These results suggest that SCI causes a rapidly developing nociceptor sensitization and peripheral inflammation that may contribute to the early emergence and persistence of chronic SCI pain.

GABAergic system disinhibition played an important role in the pathogenesis of remifentanil-induced hyperalgesia (RIH). K-Cl-cotransporter-2 (KCC2) has the potential to enhance the strength of GABAergic signaling function. However, few reports have focused on the additive analgesic effect of KCC2 enhancer and GABAA receptor agonist on the spinal dorsal horn. Therefore, we evaluated the role of GABA type A receptor (GABAAR) agonist (muscimol), KCC2 enhancer (CLP257) in remifentanil-induced hyperalgesia, as well as GABA and KCC2 receptors responses in the dorsal spinal horn. Remifentanil started to reduce paw withdrawal mechanical thresholds at postoperative 4 h and lasted to 72 h. The RIH associated decreases in spinal GABA release was transient. The amount of spinal GABA transmitter by microdialysis was observed to be decreased at the beginning and reached bottom at 150 min, then returned to the baseline level at 330 min. The synthesis and transportation of GABA transmitter were inhibited, characterized as spinal GAD67 and GAT1 downregulation after the establishment of RIH model. The effect of RIH on GABA receptor downregulation was linked to the reduced expression of spinal KCC2 receptor. This decrease in KCC2 expression has coincided with an early loss of GABA inhibition. KCC2 enhancer, which is reported to lead to a reduction in intracellular Cl, can enhance GABA-mediated inhibitory function. Both muscimol and CLP257 could dose-dependently inhibit mechanical hypersensitivity caused by remifentanil-induced downregulation of GABAAα2R and KCC2, respectively. Compared with muscimol acting alone, the joint action of CLP257 and muscimol showed a higher pain threshold and less c-fos expression via upregulation of KCC2 and GABAAα2R. Taken together, these findings suggested that the RIH was initiated by decreased GABA release. Downregulation of GABAAα2R and KCC2 receptor contributed to spinally mediated hyperalgesia in RIH. KCC2 enhancer was proved to potentiate antinociceptive effect of GABAAR agonist in RIH.

To highlight and discuss the term "refractory" when used to describe pain conditions and its application to orofacial pain, as well as to highlight the factors that must be considered in a refractory patient.