Pain
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Chronic pain results in considerable suffering, as well as significant economic and societal costs. Previous evidence suggests that Native Americans (NAs) have higher rates of chronic pain than other U. S. racial or ethnic groups, but the mechanisms contributing to this pain disparity are poorly understood. ⋯ Moreover, serial mediation models identified several potential pathways to chronic pain onset within the NA group. These paths included perceived discrimination, psychological stress, pain-related anxiety, a composite measure of cardiometabolic risk, and impaired descending inhibition of spinal nociception (assessed from conditioned pain modulation of the nociceptive flexion reflex). These results provide the first prospective evidence for a pain disparity in NAs that seems to be promoted by psychosocial, cardiometabolic, and pronociceptive mechanisms.
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CB2 cannabinoid receptors (CB2) are a promising therapeutic target that lacks unwanted side effects of CB1 activation. However, the cell types expressing CB2 that mediate these effects remain poorly understood. We used transgenic mice with CB2 promoter-driven expression of enhanced green fluorescent protein (EGFP) to study cell types that express CB2 and suppress neuropathic nociception in a mouse model of chemotherapy-induced peripheral neuropathy. ⋯ EGFP fluorescence was also expressed in dendritic cells in the dermis, Langerhans cells in the epidermis, and Merkel cells. Quantification of the EGFP signal revealed that Langerhans cells were dynamically increased in the epidermis after paclitaxel treatment. Our studies implicate CB2 expressed in previously unrecognized populations of skin cells as a potential target for suppressing chemotherapy-induced neuropathic nociception.
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Networks of the dorsal horn of the spinal cord process nociceptive information from the periphery. In these networks, the excitation-inhibition balance is critical to shape this nociceptive information and to gate it to the brain where it is interpreted as pain. Our aim was to define whether short-term plasticity of inhibitory connections could tune this inhibition-excitation balance by differentially controlling excitatory and inhibitory microcircuits. ⋯ Interestingly, the balance favors inhibition at frequencies associated with intense pain, whereas it favors excitation at frequencies associated with low pain. Therefore, these target-specific and frequency-specific plasticities allow to tune the balance between inhibition and disinhibition while processing frequency-coded information from primary afferents. These short-term plasticities and their modulation by A1 and GABAB receptors might represent an interesting target in pain-alleviating strategies.
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Concomitant use of pregabalin with opioids and/or benzodiazepines is common, despite the increased risks. However, clinical trials suggest pregabalin can have an opioid-sparing effect when treating acute postoperative pain. We explored how opioid and benzodiazepine use changed over time in people initiating pregabalin, using dispensing claims data for a 10% sample of Australians (2013-19). ⋯ Among people using both opioids and pregabalin, the geometric mean daily dose in oral morphine equivalents increased after pregabalin initiation in all trajectories, ranging from +5.9% (99% confidence interval 4.8%-7.0%) to +39.8% (99% confidence interval 38.3%-41.5%) in people on the highest daily pregabalin dose. Among people using both pregabalin and benzodiazepines, the dose remained constant over time for people in all trajectories. Notwithstanding its reputation as opioid-sparing, in this outpatient setting, we observed that people using opioids tended to use higher opioid daily doses after pregabalin initiation, especially those on high pregabalin doses.
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Endogenous pain modulation, as tested by the conditioned pain modulation (CPM) protocol, is typically less efficient in patients with chronic pain compared with healthy controls. We aimed to assess whether CPM is less efficient in patients with painful diabetic polyneuropathy (DPN) compared with those with nonpainful DPN. Characterization of the differences in central pain processing between these 2 groups might provide a central nervous system explanation to the presence or absence of pain in diabetic neuropathy in addition to the peripheral one. ⋯ Moreover, patients who had mechanical hypoesthesia demonstrated more efficient CPMHEAT (P = 0.005). More efficient CPM among patients with painful DPN might result from not only central changes in pain modulation but also from altered sensory messages coming from tested affected body sites. This calls for the use of intact sites for proper assessment of pain modulation in patients with neuropathy.