Accepted

Ferroptosis is an inflammatory programmed cell death process that is dependent on iron deposition and lipid peroxidation. The P2X7 receptor not only is involved in the pain process but also is closely related to the onset of depression. Gallic acid (3,4,5-trihydroxybenzoic acid), which is naturally found in a variety of plants, exhibits anti-inflammatory, antioxidant, and analgesic effects. This study established a rat model with the comorbidity of chronic constrictive injury (CCI) plus chronic unpredictable mild stress (CUMS) to explore the role and mechanism of gallic acid in the treatment of pain and depression comorbidity. Our experimental results showed that pain and depression-like behaviors were more obvious in the chronic constriction injury (CCI) plus chronic unpredictable mild stimulation (CUMS) group than they were in the sham operation group, and the P2X7-reactive oxygen species (ROS) signaling pathway was activated. The tissue iron concentration was increased, and mitochondrial damage was observed in the CCI plus CUMS group. These results were alleviated with gallic acid treatment. Therefore, we speculate that gallic acid inhibits the ferroptosis of the spinal microglia by regulating the P2X7-ROS signaling pathway and relieves the behavioral changes in rats with comorbid pain and depression.

Nadine Matthie, PhD, RN, CNL is an Assistant Professor in the Nell Hodgson Woodruff School of Nursing at Emory University in Atlanta, GA, USA. As a nurse scientist, she has conducted behavioral research to investigate pain and self-management in adults living with sickle cell disease, and address chronic, non vaso-occlusive pain in this population. Dr Matthie is developing non pharmacological, patient-centered, self-management strategies that incorporate virtual reality and biopsychosocial approaches to help manage chronic pain and reduce the burden of sickle cell; thereby, facilitating new, personalized approaches to management of chronic pain conditions in the home setting. Her research has been published in several national and international peer-reviewed sources for various disciplines, including nursing, medicine, music therapy and psychology.

To study the effect of epidural dexamethasone in postoperative pain management. Random-effects meta-analysis was conducted in RevMan 5.4. We included nine randomized-controlled trials (RCT) with 657 patients. Dexamethasone demonstrated longer analgesia duration (mean difference 266.18 minutes, 95% CI [3.21,529.14]; p 0.05), lower incidence of nausea and vomiting during the first postoperative day (risk ratio 0.36, 95% CI [0.18,0.71]; p 0.004), and lower antiemetic requirements (risk ratio 0.33, 95% CI [0.14,0.79]; p 0.01). No difference in pain reduction and the length of hospital stay was observed between the groups. Dexamethasone was associated with a longer analgesic effect, a lower number of patients requiring antiemetics, and lower incidences of nausea and vomiting.

We sought to investigate the impact of social determinants of health on pain clinic attendance. Retrospective data were collected from the Pain Center at Montefiore Medical Center from 2016 to 2020 and analyzed with multivariable logistic regression. African-Americans were less likely to attend appointments compared with White patients (odds ratio [OR]: 0.73; 95% CI: 0.70-0.77; p < 0.001). Males had decreased attendance compared with females (OR: 0.89; 95% CI: 0.87-0.92; p < 0.001). Compared with Commercial, those with Medicaid (OR: 0.69; 95% CI: 0.66-0.72; p < 0.001) and Medicare (OR: 0.76; 95% CI: 0.73-0.80; p < 0.001) insurance had decreased attendance. Significant disparities exist in pain clinic attendance based upon social determinants of health including race, gender and insurance type.

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based -Cre knock-in transgenic rat that provides cell-type specific genetic access to MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the -Cre knock-in rats to study the involvement of nucleus accumbens (NAc) MOR-expressing cells in heroin self-administration in male and female rats.Using RNAscope, autoradiography, and fluorescence hybridization chain reaction (HCR-FISH), we found no differences in expression in NAc, dorsal striatum (DS), and dorsal hippocampus, or MOR receptor density (except DS) or function between -Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that is highly co-expressed with (95-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that lesions decreased acquisition of heroin self-administration in male -Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female -Cre rats.The validation of an -Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based -Cre knock-in transgenic rat that provides cell-type specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the -Cre knock-in rats to show that lesioning nucleus accumbens MOR-expressing cells had different effects on heroin self-administration in males and females. The new -Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the 'silent' cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of 'silent' cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.Pregabalin is an analgesic drug in the clinic, that is supposed to act by blocking neurotransmitter release. Here we show that silent nociceptors that are activated by chemotherapeutic insults like oxaliplatin are silenced by pregabalin, which blocks the associated pain. This mode of action suggests that peripheral acting pregabalin-like drugs could be very useful for pain during chemotherapy, as they would have no CNS side effects – a problem for many patients with pregabalin. This novel effect of pregabalin is mediated by its interaction with the α2δ1 calcium channel subunit, but how this works is not yet understood.

Prior to 2020, pain management in the Washtenaw/Livingston County Medical Control Authority (W/L MCA) Emergency Medical Service (EMS) system in Southeast Michigan was limited to morphine, fentanyl, ketorolac, and acetaminophen. Based on the increasing evidence describing its safety and efficacy, ketamine was added to local protocols for pain management. This study aimed to evaluate differences in pain management and adverse effects of ketamine and opioid administration. Data from pediatric patients who received ketamine or an opioid in the W/L MCA EMS system from October 2019 to March 2021 were analyzed. The primary outcome was the difference in pain score, and the secondary outcome was adverse effects observed after analgesic administration. The decrease in pain scores was greater among ketamine patients (mean: 5.2) compared to opioid patients (mean: 2.9),  < 0.001. The prevalence of adverse effects was higher among patients in the ketamine group (28.6%) compared to patients in the opioid group (2.4%,  < 0.001). Of 14 patients who received ketamine, one 17-year-old male experienced mild anxiety (7.1%), two teenage females experienced mild dissociation (14.3%), and one 20-year-old female experienced mild nausea (7.1%). Overall, ketamine is a safe and effective option compared to opioids for pediatric patients experiencing moderate to severe prehospital pain.