ATF3 is a neuron-specific biomarker for spinal cord injury and ischaemic stroke.

BACKGROUND: Although many molecules have been investigated as biomarkers for spinal cord injury (SCI) or ischemic stroke, none of them are specifically induced in central nervous system (CNS) neurons following injuries with low baseline expression. However, neuronal injury constitutes a major pathology associated with SCI or stroke and strongly correlates with neurological outcomes. Biomarkers characterized by low baseline expression and specific induction in neurons post-injury are likely to better correlate with injury severity and recovery, demonstrating higher sensitivity and specificity for CNS injuries compared to non-neuronal markers or pan-neuronal markers with constitutive expressions. METHODS: In animal studies, young adult wildtype and global Atf3 knockout mice underwent unilateral cervical 5 (C5) SCI or permanent distal middle cerebral artery occlusion (pMCAO). Gene expression was assessed using RNA-sequencing and qRT-PCR, while protein expression was detected through immunostaining. Serum ATF3 levels in animal models and clinical human samples were measured using commercially available enzyme-linked immune-sorbent assay (ELISA) kits. RESULTS: Activating transcription factor 3 (ATF3), a molecular marker for injured dorsal root ganglion sensory neurons in the peripheral nervous system, was not expressed in spinal cord or cortex of naïve mice but was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Additionally, ATF3 protein levels in mouse blood significantly increased 1 day after SCI or ischemic stroke. Importantly, ATF3 protein levels in human serum were elevated in clinical patients within 24 hours after SCI or ischemic stroke. Moreover, Atf3 knockout mice, compared to the wildtype mice, exhibited worse neurological outcomes and larger damage regions after SCI or ischemic stroke, indicating that ATF3 has a neuroprotective function. CONCLUSIONS: ATF3 is an easily measurable, neuron-specific biomarker for clinical SCI and ischemic stroke, with neuroprotective properties. HIGHLIGHTS: ATF3 was induced specifically in neurons of the spinal cord or cortex within 1 day after SCI or ischemic stroke, respectively. Serum ATF3 protein levels are elevated in clinical patients within 24 hours after SCI or ischemic stroke. ATF3 exhibits neuroprotective properties, as evidenced by the worse neurological outcomes and larger damage regions observed in Atf3 knockout mice compared to wildtype mice following SCI or ischemic stroke.

Mismatched Postsurgical Opioid Prescription to Liver Transplant Patients: A Retrospective Cohort Study From a Single High-volume Transplant Center.

BACKGROUND: Improper opioid prescription after surgery is a well-documented iatrogenic contributor to the current opioid epidemic in North America. In fact, opioids are known to be overprescribed to liver transplant patients, and liver transplant patients with high doses or prolonged postsurgical opioid use have higher risks of graft failure and death. METHODS: This is a retrospective cohort study of 552 opioid-naive patients undergoing liver transplant at an academic center between 2012 and 2019. The primary outcome was the discrepancy between the prescribed discharge opioid daily dose and each patient's own inpatient opioid consumption 24 h before discharge. Variables were analyzed with Wilcoxon and chi-square tests and logistic regression. RESULTS: Opioids were overprescribed in 65.9% of patients, and 54.3% of patients who required no opioids the day before discharge were discharged with opioid prescriptions. In contrast, opioids were underprescribed in 13.4% of patients, among whom 27.0% consumed inpatient opioids but received no discharge opioid prescription. The median prescribed opioid daily dose was 333.3% and 56.3% of the median inpatient opioid daily dose in opioid overprescribed and underprescribed patients, respectively. Importantly, opioid underprescribed patients had higher rates of opioid refill 1 to 30 and 31 to 90 d after discharge, and the rate of opioid underprescription more than doubled from 2016 to 2019. CONCLUSIONS: Opioids are both over- and underprescribed to liver transplant patients, and opioid underprescribed patients had higher rates of opioid refill. Therefore, we proposed to prescribe discharge opioid prescriptions based on liver transplant patients' inpatient opioid consumption to provide patient-centered opioid prescriptions.

Mismatched opioid prescription in patients discharged after neurological surgeries: a retrospective cohort study.

ABSTRACT: Although postsurgical overprescription has been well-studied, postsurgical opioid underprescription remains largely overlooked. This retrospective cohort study was to investigate the extent of discharge opioid overprescription and underprescription in patients after neurological surgeries. Six thousand nine hundred forty-nine adult opioid-naive patients who underwent inpatient neurosurgical procedures at the University of California San Francisco were included. The primary outcome was the discrepancy between individual patient's prescribed daily oral morphine milligram equivalent (MME) at discharge and patient's own inpatient daily MME consumed within 24 hours of discharge. Analyses include Wilcoxon, Mann-Whitney, Kruskal-Wallis, and χ 2 tests, and linear or multivariable logistic regression. 64.3% and 19.5% of patients were opioid overprescribed and underprescribed, respectively, with median prescribed daily MME 360% and 55.2% of median inpatient daily MME in opioid overprescribed and underprescribed patients, respectively. 54.6% of patients with no inpatient opioid the day before discharge were opioid overprescribed. Opioid underprescription dose-dependently increased the rate of opioid refill 1 to 30 days after discharge. From 2016 to 2019, the percentage of patients with opioid overprescription decreased by 24.8%, but the percentage of patients with opioid underprescription increased by 51.2%. Thus, the mismatched discharge opioid prescription in patients after neurological surgeries presented as both opioid overprescription and underprescription, with a dose-dependent increased rate of opioid refill 1 to 30 days after discharge in opioid underprescription. Although we are fighting against opioid overprescription to postsurgical patients, we should not ignore postsurgical opioid underprescription.

Opioid Overprescription and Underprescription to Patients After Otolaryngology-Head and Neck Surgery.

This cohort study examines the extent of mismatched opioid prescribing between hospitalization and discharge after otolaryngology­head and neck surgery.

A Procedure for Mouse Dorsal Root Ganglion Cryosectioning.

High-quality mouse dorsal root ganglion (DRG) cryostat sections are crucial for proper immunochemistry staining and RNAscope studies in the research of inflammatory and neuropathic pain, itch, as well as other peripheral neurological conditions. However, it remains a challenge to consistently obtain high-quality, intact, and flat cryostat sections onto glass slides because of the tiny sample size of the DRG tissue. So far, there is no article describing an optimal protocol for DRG cryosectioning. This protocol presents a step-by-step method to resolve the frequently encountered difficulties associated with DRG cryosectioning. The presented article explains how to remove the surrounding liquid from the DRG tissue samples, place the DRG sections on the slide facing the same orientation, and flatten the sections on the glass slide without curving up. Although this protocol has been developed for cryosectioning the DRG samples, it can be applied for the cryosectioning of many other tissues with a small sample size.

Discharge Opioid Over- and Underprescription to Patients after General Surgery: A Retrospective Cohort Study.

BACKGROUND: Although postoperative opioid overprescription has been well studied, little is known about opioid underprescription. This study aims to determine the extent of improper discharge opioid prescription in patients undergoing general surgery procedures. STUDY DESIGN: This retrospective cohort study investigated opioid-naïve adult patients who underwent inpatient general surgery at an academic medical center between June 2012 and December 2019. The primary outcome was the difference between individual patient's inpatient daily oral morphine milligram equivalent (MME) 24 hours before discharge and patient's prescribed daily MME at discharge. The data were analyzed using chi-square, Mann-Whitney, Wilcoxon, and Kruskal-Wallis tests and multivariable logistic regression. RESULTS: Among 5,531 patients, 58.1% had opioid overprescription, and 22.4% had opioid underprescription. Median prescribed daily MME was 311% of median inpatient daily MME in overprescribed patients and 56.3% of median inpatient daily MME in underprescribed patients. About half (52.3%) of patients who consumed no opioids on the day before discharge were opioid overprescribed, and 69.9% of patients who required inpatient daily opioid of >100 MME were opioid underprescribed. Opioid-underprescribed patients had an increased opioid refill rate 1 to 30 days after discharge, whereas opioid-overprescribed patients had an increased refill rate 31 to 60 days after discharge. From 2017 to 2019, the percentage of overprescribed patients decreased by 35.8%, but the percentage of underprescribed patients increased by 42.4%. CONCLUSIONS: Although avoiding postoperative opioid overprescription remains imperative, preventing postoperative opioid underprescription is also essential. We recommend using a patient-centered approach to match the daily dose of opioid prescription with each patient's inpatient daily opioid consumption.

Racial Differences in Postoperative Opioid Prescribing Practices in Spine Surgical Patients.

BACKGROUND: As the opioid epidemic accelerates in the United States, numerous sociodemographic factors have been implicated its development and are, furthermore, a driving factor of the disparities in postoperative pain management. Recent studies have suggested potential associations between the influence of race and ethnicity on pain perception but also the presence of unconscious biases in the treatment of pain in minority patients. OBJECTIVE: To characterize the perioperative opioid requirements across racial groups after spine surgery. METHODS: A retrospective, observational study of 1944 opioid-naive adult patients undergoing a neurosurgical spine procedure, from June 2012 to December 2019, was performed at a large, quaternary care institute. Postoperative inpatient and outpatient opioid usage was measured by oral morphine equivalents, across various racial groups. RESULTS: Case characteristics were similar between racial groups. In the postoperative period, White patients had shorter lengths of stay compared with Black and Asian patients ( P < .05). Asian patients used lower postoperative inpatient opioid doses in comparison with White patients ( P < .001). White patients were discharged with significantly higher doses of opioids compared with Black patients ( P < .01); however, they were less likely to be readmitted within 30 days of discharge ( P < .01). CONCLUSION: In a large cohort of opioid-naive postoperative neurosurgical patients, this study demonstrates higher inpatient and outpatient postoperative opioid usage among White patients. Increasing physician awareness to the effect of race on inpatient and outpatient pain management would allow for a modified opioid prescribing practice that ensures limited yet effective opioid dosages void of implicit biases.

The Role of Neuro-Immune Interactions in Chronic Pain: Implications for Clinical Practice.

Chronic pain remains a public health problem and contributes to the ongoing opioid epidemic. Current pain management therapies still leave many patients with poorly controlled pain, thus new or improved treatments are desperately needed. One major challenge in pain research is the translation of preclinical findings into effective clinical practice. The local neuroimmune interface plays an important role in the initiation and maintenance of chronic pain and is therefore a promising target for novel therapeutic development. Neurons interface with immune and immunocompetent cells in many distinct microenvironments along the nociceptive circuitry. The local neuroimmune interface can modulate the activity and property of the neurons to affect peripheral and central sensitization. In this review, we highlight a specific subset of many neuroimmune interfaces. In the central nervous system, we examine the interface between neurons and microglia, astrocytes, and T lymphocytes. In the periphery, we profile the interface between neurons in the dorsal root ganglion with T lymphocytes, satellite glial cells, and macrophages. To bridge the gap between preclinical research and clinical practice, we review the preclinical studies of each neuroimmune interface, discuss current clinical treatments in pain medicine that may exert its action at the neuroimmune interface, and highlight opportunities for future clinical research efforts.

Opioid prescribing practices at hospital discharge for surgical patients before and after the Centers for Disease Control and Prevention's 2016 opioid prescribing guideline.

BACKGROUND: The Centers for Disease Control and Prevention's (CDC) March 2016 opioid prescribing guideline did not include prescribing recommendations for surgical pain. Although opioid over-prescription for surgical patients has been well-documented, the potential effects of the CDC guideline on providers' opioid prescribing practices for surgical patients in the United States remains unclear. METHODS: We conducted an interrupted time series analysis (ITSA) of 37,009 opioid-naïve adult patients undergoing inpatient surgery from 2013-2019 at an academic medical center. We assessed quarterly changes in the discharge opioid prescription days' supply, daily and total doses in oral morphine milligram equivalents (OME), and the proportion of patients requiring opioid refills within 30 days of discharge. RESULTS: The discharge opioid prescription declined by -0.021 (95% CI, -0.045 to 0.003) days per quarter pre-guideline versus -0.201 (95% CI, -0.223 to -0.179) days per quarter post-guideline (p < 0.0001). Likewise, the mean daily and total doses of the discharge opioid prescription declined by -0.387 (95% CI, -0.661 to -0.112) and -7.124 (95% CI, -9.287 to -4.962) OME per quarter pre-guideline versus -2.307 (95% CI, -2.560 to -2.055) and -20.68 (95% CI, -22.66 to -18.69) OME per quarter post-guideline, respectively (p < 0.0001). Opioid refill prescription rates remained unchanged from baseline. CONCLUSIONS: The release of the CDC opioid guideline was associated with a significant reduction in discharge opioid prescriptions without a concomitant increase in the proportion of surgical patients requiring refills within 30 days. The mean prescription for opioid-naïve surgical patients decreased to less than 3 days' supply and less than 50 OME per day by 2019.

Neuroanatomical Basis for the Orexinergic Modulation of Anesthesia Arousal and Pain Control.

Hypothalamic orexin (hypocretin) neurons play crucial roles in arousal control. Their involvement in anesthesia and analgesia remains to be better understood. In order to enhance our view on the neuroanatomy, we systematically mapped the projections of orexin neurons with confocal microscope and light sheet microscope. We specifically expressed optogenetic opsins tagged with fluorescence markers in orexin neurons through adeno-associated viral infection in the mouse brain. The imaging results revealed fine details and novel features of the orexin projections throughout the brain, particularly related to the nuclei regulating arousal and pain. We then optogenetically activated orexin neurons in the lateral hypothalamus to study the effects on anesthesia-related behaviors. cFos staining showed that optogenetic stimulation can activate orexin neurons in the ChR2-mCherry group, but not the control mCherry group (62.86 ± 3.923% vs. 7.9 ± 2.072%; P < 0.0001). In behavior assays, optogenetic stimulation in the ChR2-mCherry group consistently elicited robust arousal from light isoflurane anesthesia (9.429 ± 3.804 s vs. 238.2 ± 17.42 s; P < 0.0001), shortened the emergence time after deep isoflurane anesthesia (109.5 ± 13.59 s vs. 213.8 ± 21.77 s; P = 0.0023), and increased the paw withdrawal latency in a hotplate test (11.45 ± 1.185 s vs. 8.767 ± 0.7775; P = 0.0317). The structural details of orexin fibers established the neuroanatomic basis for studying the role of orexin in anesthesia and analgesia.

Identification of Foramen Ovale With H-Figure Fluoroscopic Landmark Improves Treatment Outcomes in Idiopathic Trigeminal Neuralgia.

BACKGROUND: Because it is traditionally difficult and time-consuming to identify the foramen ovale (FO) with fluoroscopy, we recently developed the H-figure method to acquire fluoroscopic view of FO with shorter procedure time and less radiation. However, the impact of such an H-figure approach on the clinical outcomes of trigeminal ganglion radiofrequency thermocoagulation (RFT) in treating idiopathic trigeminal neuralgia (ITN) remains unclear. METHODS: In a 12-month follow-up retrospective cohort study, patients with ITN had fluoroscopy-guided RFT of trigeminal ganglion via either classic approach (n = 100) or H-figure approach (n = 136) to identify FO. Data of continuous variables were analyzed with a Shapiro-Wilk test for normality and subsequently with a Mann-Whitney test, and the binary data were analyzed with a χ 2 test. The primary outcome was the facial pain measured by a Visual Analog Scale (VAS) 1 year after the treatment. The secondary outcomes included the quality of the fluoroscopic FO views, the threshold voltage to provoke paresthesia, the procedure time, the number of fluoroscopic images, and the facial numbness VAS. RESULTS: Compared with the classic approach group, the H-figure approach group was associated with better long-term pain relief after the procedure, with significantly fewer patients had pain 3 months (6.6% vs 17.0%, P = .012) and 12 months (21.3% vs 38.0%, P = .005) after the procedure, and among patients who had pain after the procedure, patients in the H-figure group had significantly less pain 6 months after the procedure (VAS median [interquartile range (IQR)]: 3 [2-6] vs 6 [4-7], P < .001). Moreover, compared to the classic approach, the H-figure approach provided better fluoroscopic view of FO, lower threshold voltage to elicit paresthesia (median [IQR]: 0.2 [0.2-0.3] vs 0.4 [0.4-0.5] V, P < .0001), with shorter procedure time (median [IQR]: 7.5 [6.0-9.0] vs 14.0 [10.0-18.0] min, P < .0001), and required fewer fluoroscopic images (median [IQR]: 4.0 [3.0-5.0] vs 8.0 [6.0-10.0], P < .0001). CONCLUSIONS: RFT of the trigeminal ganglion using the H-figure approach is associated with superior longer term clinical pain relief than the classic approach in treating ITN.

Distinct phases of adult microglia proliferation: a Myc-mediated early phase and a Tnfaip3-mediated late phase.

Microgliosis is a hallmark of many neurological diseases, including Alzheimer's disease, stroke, seizure, traumatic brain and spinal cord injuries, and peripheral and optic nerve injuries. Recent studies have shown that the newly self-renewed microglia have specific neurological functions. However, the mechanism of adult microglia proliferation remains largely unclear. Here, with single-cell RNA sequencing, flow cytometry, and immunohistochemistry, we demonstrate that the sciatic nerve injury induced two distinct phases of microglia proliferation in mouse spinal cord, each with different gene expression profiles. We demonstrate that the transcription factor Myc was transiently upregulated in spinal cord microglia after nerve injury to mediate an early phase microglia proliferation. On the other hand, we reveal that the tumor-necrosis factor alpha-induced protein 3 (Tnfaip3) was downregulated to mediate the Myc-independent late-phase microglia proliferation. We show that cyclin dependent kinase 1, a kinase with important function in the M phase of the cell cycle, was involved only in the early phase. We reveal that although the early phase was neither necessary nor sufficient for the late phase proliferation, the late-phase suppressed the early phase microglia proliferation in the spinal cord. Finally, we demonstrate that the termination of spinal cord microglia proliferation required both Myc and Tnfaip3 to resume their baseline expression. Thus, we have delineated an interactive signaling network in the proliferation of differentiated microglia.

Modified Spared Nerve Injury Surgery Model of Neuropathic Pain in Mice.

Spared nerve injury (SNI) is an animal model that mimics the cardinal symptoms of peripheral nerve injury for studying the molecular and cellular mechanism of neuropathic pain in mice and rats. Currently, there are two types of SNI model, one to cut and ligate the common peroneal and the tibial nerves with intact sural nerve, which is defined as SNIs in this study, and another to cut and ligate the common peroneal and the sural nerves with intact tibial nerve, which is defined as SNIt in this study. Because the sural nerve is purely sensory whereas the tibial nerve contains both motor and sensory fibers, the SNIt model has much less motor deficit than the SNIs model. In the traditional SNIt mouse model, the common peroneal and the sural nerves are cut and ligated separately. Here a modified SNIt surgery method is described to damage both common peroneal and sural nerves with only one ligation and one cut with a shorter procedure time, which is easier to perform and reduces the potential risk of stretching the sciatic or tibial nerves, and produces similar mechanical hypersensitivity as the traditional SNIt model.

Function of Oncogene Mycn in Adult Neurogenesis and Oligodendrogenesis.

Human MYCN is an oncogene amplified in neuroblastoma and many other tumors. Both human MYCN and mouse Mycn genes are important in embryonic brain development, but their functions in adult healthy nerve system are completely unknown. Here, with Mycn-eGFP mice and quantitative RT-PCR, we found that Mycn was expressed in specific brain regions of young adult mice, including subventricular zone (SVZ), subgranular zone (SGZ), olfactory bulb (OB), subcallosal zone (SCZ), and corpus callosum (CC). With immunohistochemistry (IHC), we found that many Mycn-expressing cells expressed neuroblast marker doublecortin (DCX) and proliferation marker Ki67. With Dcx-creER and Mki67-creER mouse lines, we fate mapped Dcx-expressing neuroblasts and Mki67-expressing proliferation cells, along with deleting Mycn from these cells in adult mice. We found that knocking out Mycn from adult neuroblasts or proliferating cells significantly reduced cells in proliferation in SVZ, SGZ, OB, SCZ, and CC. We also demonstrated that the Mycn-deficient neuroblasts in SGZ matured quicker than wild-type neuroblasts, and that Mycn-deficient proliferating cells were more likely to survive in SVZ, SGZ, OB, SCZ, and CC compared to wild type. Thus, our results demonstrate that, in addition to causing tumors in the nervous system, oncogene Mycn has a crucial function in neurogenesis and oligodendrogenesis in adult healthy brain.

Contribution of colony-stimulating factor 1 to neuropathic pain.

Molecular and cellular interactions among spinal dorsal horn neurons and microglia, the resident macrophages of the central nervous system, contribute to the induction and maintenance of neuropathic pain after peripheral nerve injury. Emerging evidence also demonstrates that reciprocal interactions between macrophages and nociceptive sensory neurons in the dorsal root ganglion contribute to the initiation and persistence of nerve injury-induced mechanical hypersensitivity (allodynia). We previously reported that sensory neuron-derived colony-stimulating factor 1 (CSF1), by engaging the CSF1 receptor (CSF1R) that is expressed by both microglia and macrophages, triggers the nerve injury-induced expansion of both resident microglia in the spinal cord and macrophages in the dorsal root ganglion and induces their respective contributions to the neuropathic pain phenotype. Here, we review recent research and discuss unanswered questions regarding CSF1/CSF1R-mediated microglial and macrophage signaling in the generation of neuropathic pain.

Novel fluoroscopic landmark to significantly facilitate the visualization of foramen ovale in treating idiopathic trigeminal neuralgia.

BACKGROUND AND OBJECTIVES: Access through the foramen ovale (FO) is essential in performing trigeminal ganglion injection, glycerol rhizolysis, balloon compression, and radiofrequency thermocoagulation (RFT) to treat idiopathic trigeminal neuralgia (ITN). However, identification of the FO under fluoroscopy can be difficult and time-consuming, and thus exposes patients to increased radiation and procedure risks. Here we present the 'H-figure' as a novel fluoroscopic landmark to quickly visualize the FO. METHODS: The H-figure landmark can be recognized as the medial border of the mandible and the lateral edge of the maxilla as the two vertical lines, and the superior line of petrous ridge of temporal bone (S-P-T line) as the horizontal line, and the FO fluoroscopic view is then optimized at the center of the H-figure immediately above the S-P-T line. We applied this landmark in a clinical cohort of 136 patients with ITN who underwent fluoroscopy-guided RFT of the trigeminal ganglion. We also compared the H-figure method with the traditional method. The primary outcome was the total number of fluoroscopic images required to visualize the FO (as a proxy of radiation exposure). Secondary measures included the procedure time required to finalize the FO view and the sensory testing voltage for paresthesia. RESULTS: With the H-figure approach we were able to view the FO with an average of 4.2 fluoroscopic shots at an average time of 6.8 min. When compared with the non-H-figure traditional technique, the H-figure method required almost half the fluoroscopic shots in nearly half the procedure duration time, and paresthesia was evoked with half of the voltage. CONCLUSION: The H-figure is an easy fluoroscopic landmark that can help to view the FO with less radiation and procedure time, and the needles placed with this approach can be closer to the target for the RFT treatment of patients with ITN.

Ion Channels in Anesthesia.

Ion channels play a pivotal role in anesthesia, including general and regional anesthesia. Two main classes of general anesthetics (GAs) are inhalational anesthetics, such as isoflurane, sevoflurane, and nitrous oxide; injectable anesthetics, such as propofol, etomidate, and ketamine. Besides hypnotic agents, muscle relaxants for immobility and opioids for analgesia are needed to achieve balanced anesthesia. Although our understanding of anesthesia is far from complete, recent studies have revealed the molecular interactions between anesthetic drugs and ion channels, particularly, the ligand-gated ion channels (LGICs). Ionotropic GABAA receptors (GABAARs), the main mediators of the inhibitory signals in the central nervous system (CNS), are the key to hypnosis by general anesthetics. Ionotropic cholinergic receptors (nAChRs), expressed at the neuromuscular junction and the nervous system, are the molecular targets of muscle relaxants. GABAARs and nAChRs belong to the same family of pentameric LGICs. With a completely different architecture, ionotropic glutamate receptors (iGluRs) carry the excitatory signals in the CNS and are targeted by inhalational anesthetics and ketamine. Another distinct family of ion channels, two-pore-domain K+ (K2P) channels, can be activated by inhalational anesthetics and cause neuron hyperpolarization. In this chapter, we will discuss the recent advance in understanding the molecular mechanisms underlying anesthesia through the molecular structures of these ion channels.

Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain.

Paralleling the activation of dorsal horn microglia after peripheral nerve injury is a significant expansion and proliferation of macrophages around injured sensory neurons in dorsal root ganglia (DRG). Here we demonstrate a critical contribution of DRG macrophages, but not those at the nerve injury site, to both the initiation and maintenance of the mechanical hypersensitivity that characterizes the neuropathic pain phenotype. In contrast to the reported sexual dimorphism in the microglial contribution to neuropathic pain, depletion of DRG macrophages reduces nerve injury-induced mechanical hypersensitivity and expansion of DRG macrophages in both male and female mice. However, fewer macrophages are induced in the female mice and deletion of colony-stimulating factor 1 from sensory neurons, which prevents nerve injury-induced microglial activation and proliferation, only reduces macrophage expansion in male mice. Finally, we demonstrate molecular cross-talk between axotomized sensory neurons and macrophages, revealing potential peripheral DRG targets for neuropathic pain management.