Mol Pain
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Although elevated estradiol levels facilitate chronic pelvic pain in animal models, it remains to be determined whether sex steroid levels are altered in a cross-section of women with chronic pelvic pain (CPP) and those at-risk for developing CPP. We sought to determine if sex steroid levels are increased in women with menstrual pain and whether those changes were more extreme in two groups of women with worsened pelvic pain profiles: a) dysmenorrhea plus evidence of bladder pain sensitivity and b) bladder pain syndrome. Serum samples were collected during the mid-luteal phase to measure estradiol, progesterone, testosterone, and sex hormone-binding globulin. ⋯ Levels of pain sensitivity and mood were different across the groups, but the only significant relationship to sex steroids was that sex hormone-binding globulin was correlated to somatic symptoms (r = 0.26, p = 0.03). These findings show women potentially at-risk for CPP and women with diagnosed CPP exhibit altered circulating levels of sex steroids. Because these hormonal differences appear to be independent of mood or pain sensitivity, the role of sex steroids in the emergence of CPP may be via sensitization of visceral afferents.
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Complex regional pain syndrome (CRPS) is a progressive and painful disease of the extremities that is characterized by continuous pain inconsistent with the initial trauma. CRPS is caused by a multi-mechanism process that involves both the peripheral and central nervous system, with a prominent role of inflammation in CRPS pathophysiology. This review examines what is currently known about the CRPS inflammatory and pain mechanisms, as well as the possible impact of neurostimulation therapies on the neuroimmune axis of CRPS. ⋯ Increasing evidence supports a role for inflammation and neuroinflammation in CRPS pathophysiology. Preliminary neurostimulation findings, together with the role of (neuro)inflammation in CRPS, seems to provide a compelling rationale for its use in CRPS pain treatment. The possible immunomodulatory effects of neurostimulation opens new therapeutic possibilities, however further research is needed to gain a better understanding of the working mechanisms.
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Microglia activation following peripheral nerve injury has been shown to contribute to central sensitization of the spinal cord for the development of neuropathic pain. In a recent study, we reported that the amount of nerve damage does not necessarily correlate with chronic pain development. Here we compared the response of spinal microglia, using immunohistochemistry as a surrogate of microglial activation, in mice with two different types of crush injury of the sciatic nerve. ⋯ Ipsilateral Iba-1 reactivity was comparable between injuries at 7 days with a significant increase compared to the contralateral side. By day 15 after injury, ipsilateral Iba-1 immunoreactivity was much reduced compared to day 7 and was not different between the groups. Our results suggest that the magnitude of the early microgliosis is dependent on injury severity, but does not necessarily correlate with the long-term development of chronic pain-like hypersensitivity after peripheral nerve injury.
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Long-term potentiation (LTP) is an important molecular mechanism for chronic pain in the anterior cingulate cortex (ACC), a key cortical region for pain perception and emotional regulation. Inhibiting ACC LTP via various manipulations or pharmacological treatments blocks chronic pain. Long-term depression (LTD) is another form of synaptic plasticity in the ACC, which is also proved to be involved in the mechanisms of chronic pain. ⋯ Furthermore, NMDA receptor antagonist AP-5 blocked the induction of synaptic depression after potentiation. The GluN2B-selective antagonist Ro25-6981 also inhibited the phenomenon in the ACC, while the GluN2A-selective antagonist NVP-AAM077 and the GluN2C/D-selective antagonist PPDA and UBP145 had no any significant effect. These results suggest that synaptic LTP can be depressed by LTD in a time dependent manner, and GluN2B-containing NMDA receptors play important roles in this form of synaptic depression.
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Neuropathic injury is accompanied by chronic inflammation contributing to the onset and maintenance of pain after an initial insult. In addition to their roles in promoting immune cell activation, inflammatory mediators like secretory phospholipase A2 (sPLA2) modulate nociceptive and excitatory neuronal signaling during the initiation of pain through hydrolytic activity. Despite having a known role in glial activation and cytokine release, it is unknown if sPLA2 contributes to the maintenance of painful neuropathy and spinal hyperexcitability later after neural injury. ⋯ Spinal sPLA2 inhibition at day 7 abolishes behavioral sensitivity, reduces both evoked and spontaneous neuronal firing in the spinal cord, and restores the distribution of neuronal phenotypes to those of control conditions. Inhibiting spinal sPLA2 also increases intracellular glutamate concentrations and restores spinal expression of GLAST, GLT1, mGluR5, and GluR1 to uninjured expression with no effect on NR1. These findings establish a role for spinal sPLA2 in maintaining pain and central sensitization after neural injury and suggest this may be via exacerbating glutamate excitotoxicity in the spinal cord.