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Accumulating evidence suggests hippocampal impairment under chronic pain phenotype. However, it is unknown whether neuropathic behaviors are related to dysfunction of the hippocampal circuitry. Here we enhanced hippocampal activity by pharmacological, opto- and chemo-genetic techniques to determine hippocampal influence on neuropathic pain behaviors. We found that excitation of the dorsal (DH), but not the ventral (VH), hippocampus induces analgesia in two rodent models of neuropathic pain (SNI and SNL), and in rats and mice. Optogenetic and pharmacological manipulations of DH neurons demonstrated that DH-induced analgesia was mediated by NMDA and μ-opioid receptors. In addition to analgesia, optogenetic stimulation of DH in SNI mice also resulted in enhanced real-time conditioned place preference for the chamber where DH was activated, a finding consistent with pain relief. Similar manipulations in VH were ineffective. Using chemo-fMRI, where awake resting-state fMRI was combined with viral vector mediated chemogenetic activation (PSAM/PSEM) of DH neurons, we demonstrated changes of functional connectivity between DH and thalamus and somatosensory regions that tracked the extent of relief from tactile allodynia. Moreover, we examined hippocampal functional connectivity in humans, and observe differential reorganization of its anterior and posterior subdivisions between subacute and chronic backpain. Altogether, these results imply that downregulation of DH circuitry during chronic neuropathic pain aggravates pain-related behaviors. Conversely, activation of DH reverses pain-related behaviors through local excitatory and opioidergic mechanisms affecting DH functional connectivity. Thus, the present study exhibits a novel causal role for the DH but not VH in controlling neuropathic pain-related behaviors.
Learn More >Biologic factors that predict risk for and mediate the development of common outcomes of trauma exposure such as chronic posttraumatic pain (CPTP) are poorly understood. In the current study, we examined whether peritraumatic circulating 17β-estradiol (E2) levels influence CPTP trajectories. 17β-estradiol levels were measured in plasma samples (n = 254) collected in the immediate aftermath of trauma exposure from 3 multiethnic longitudinal cohorts of men and women trauma survivors. Chronic posttraumatic pain severity was evaluated 6 weeks, 6 months, and 1 year after traumatic stress exposure. Repeated measures mixed models were used to test the relationship between peritraumatic E2 levels and prospective CPTP. Secondary analyses in a nested cohort assessed the influence of participant body mass index on the E2-CPTP relationship. In women, a statistically significant inverse relationship between peritraumatic E2 and CPTP was observed (β = -0.280, P = 0.043) such that higher E2 levels predicted lower CPTP severity over time. Secondary analyses identified an E2 * body mass index interaction in men from the motor vehicle collision cohort such that obese men with higher E2 levels were at greater risk of developing CPTP. In nonobese men from the motor vehicle collision cohort and in men from the major thermal burn injury cohort, no statistically significant relationship was identified. In conclusion, peritraumatic circulating E2 levels predict CPTP vulnerability in women trauma survivors. In addition, these data suggest that peritraumatic administration of E2 might improve CPTP outcomes for women; further research is needed to test this possibility.
Learn More >Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein.
Learn More >Data from the Global Burden of Disease Study 2019 were used to report the burden of migraine in 204 countries and territories during the period 1990 to 2019, through a systematic analysis of point prevalence, annual incidence, and years lived with disability (YLD). In 2019, the global age-standardised point prevalence and annual incidence rate of migraine were 14,107.3 (95% Uncertainty Interval [UI] 12,270.3-16,239) and 1142.5 (95% UI 995.9-1289.4) per 100,000, an increase of 1.7% (95% UI 0.7%-2.8%) and 2.1% (95% UI 1.1%-2.8%) since 1990, respectively. Moreover, the global age-standardised YLD rate in 2019 was 525.5 (95% UI 78.8-1194), an increase of 1.5% (95% UI -4.4% to 3.3%) since 1990. The global point prevalence of migraine in 2019 was higher in females and increased by age up to the 40 to 44 age group, then decreased with increased age. Belgium (22,400.6 [95% UI: 19,305.2-26,215.8]), Italy (20,337.7 [95% UI: 17,724.7-23,405.8]), and Germany (19,436.4 [95% UI: 16,806.2-22,810.3]) had the 3 highest age-standardised point prevalence rates for migraine in 2019. In conclusion, there were large intercountry differences in the burden of migraine, and this burden increased significantly across the measurement period. These findings suggest that migraine care needs to be included within the health system to increase population awareness regarding the probable risk factors and treatment strategies especially among young adults and middle-aged women, as well as to increase the data on migraines.
Learn More >The clinical impact of postoperative opioid use requires accurate prediction strategies to identify at-risk patients. We utilize preoperative claims data to predict postoperative opioid refill and new persistent use in opioid-naïve patients.
Learn More >Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein.
Learn More >Given the complex and unclear etiology of neck pain, it is important to understand the differences in central sensitization as well as psychosocial factors in individuals with chronic neck pain and healthy controls. The purpose of this study was to benchmark differences in central sensitization, psychosocial factors, and range of motion between people with nonspecific chronic neck pain and healthy controls and to analyze the correlation between pain intensity, neck disability, and psychosocial factors in people with chronic neck pain.
Learn More >Peripheral neuropathy is the most frequent dose-limiting adverse effect of oxaliplatin. Acute pain symptoms that are induced or exacerbated by cold occur in almost all patients immediately following the first infusions. Evidence has shown that oxaliplatin causes ion channel expression modulations in dorsal root ganglia neurons, which are thought to contribute to peripheral hypersensitivity. Most dysregulated genes encode ion channels involved in cold and mechanical perception, noteworthy members of a sub-group of potassium channels of the K2P family, TREK and TRAAK. Downregulation of these K2P channels has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. We investigated the molecular mechanisms underlying this peripheral dysregulation in a murine model of neuropathic pain triggered by a single oxaliplatin administration. We found that oxaliplatin-mediated TREK-TRAAK downregulation, as well as downregulation of other K channels of the K2P and Kv families, involves a transcription factor known as the neuron-restrictive silencer factor (NRSF) and its epigenetic co-repressors histone deacetylases (HDACs). NRSF knockdown was able to prevent most of these K channel mRNA downregulation in mice dorsal root ganglion neurons as well as oxaliplatin-induced acute cold and mechanical hypersensitivity. Interestingly, pharmacological inhibition of class I HDAC reproduces the antinociceptive effects of NRSF knockdown and leads to an increased K channel expression in oxaliplatin-treated mice.
Learn More >Although macrophages (MΦ) are known to play a central role in neuropathic pain, their contribution to cancer pain has not been established. Here we report that depletion of sciatic nerve resident MΦs (rMΦ) in mice attenuates mechanical/cold hypersensitivity and spontaneous pain evoked by intraplantar injection of melanoma or lung carcinoma cells. MΦ-colony stimulating factor (M-CSF) was upregulated in the sciatic nerve trunk and mediated cancer-evoked pain via rMΦ expansion, transient receptor potential ankyrin 1 (TRPA1) activation, and oxidative stress. Targeted deletion of Trpa1 revealed a key role for Schwann cell TRPA1 in sciatic nerve rMΦ expansion and pain-like behaviors. Depletion of rMΦs in a medial portion of the sciatic nerve prevented pain-like behaviors. Collectively, we identified a feed-forward pathway involving M-CSF, rMΦ, oxidative stress and Schwann cell TRPA1 that operates throughout the nerve trunk to signal cancer-evoked pain.
Learn More >Historically, marginalized patients were prescribed less opioid medication than affluent, white patients. However, because of persistent differential access to non-opioid pain treatments, this direction of disparity in opioid prescribing may have reversed.
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