The journal of pain : official journal of the American Pain Society
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Pain processing and attention have a bidirectional interaction that depends upon one's relative ability to use limited-capacity resources. However, correlations between the size of limited-capacity resources and pain have not been evaluated. Working memory capacity, which is a cognitive resource, can be measured using the reading span task (RST). In this study, we hypothesized that an individual's potential working memory capacity and subjective pain intensity are related. To test this hypothesis, we evaluated 31 healthy participants' potential working memory capacity using the RST, and then applied continuous experimental heat stimulation using the listening span test (LST), which is a modified version of the RST. Subjective pain intensities were significantly lower during the challenging parts of the RST. The pain intensity under conditions where memorizing tasks were performed was compared with that under the control condition, and it showed a correlation with potential working memory capacity. These results indicate that working memory capacity reflects the ability to process information, including precise evaluations of changes in pain perception. ⋯ In this work, we present data suggesting that changes in subjective pain intensity are related, depending upon individual potential working memory capacities. Individual working memory capacity may be a phenotype that reflects sensitivity to changes in pain perception.
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Patients with irritable bowel syndrome (IBS) are affected by chronic abdominal pain and show decreased pain inhibition. Moreover, they exhibit differences in brain morphology compared with healthy volunteers. The aim of this study was to examine whether decreased pain inhibition is associated with altered brain morphology in IBS patients. Structural magnetic resonance imaging scans were acquired in 14 female patients with diarrhea-predominant IBS and 14 controls. Pain and anxiety modulation were characterized using electrical stimulation of the sural nerve and heterotopic noxious counterstimulation. IBS patients reported decreased pain inhibition (P = .02) as well as increased shock anxiety, pain catastrophizing, depressive symptoms, and trait anxiety (P's ≤ .05). IBS patients also showed a thicker right posterior insula (pINS), associated with longer IBS duration (r = .67, P = .02). In addition, thicker right lateral orbitofrontal cortex was strongly associated with less pain inhibition in both IBS patients (r = .70, P = .02) and controls (r = .68, P = .01). Results are consistent with the role of the insula in interoception and pain and suggest that IBS may induce thickening of the pINS. Reduced pain inhibition may further involve a modification of the regulatory influence of the orbitofrontal cortex on pain-related processes. ⋯ This study investigated the brain morphology of IBS patients. IBS patients showed thicker right pINS, associated with longer disease duration but not with psychological symptoms. This suggests that IBS induces thickening of pINS, which may contribute to its pathophysiology, consistent with the role of the pINS in interoception and pain.
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Early-life stress is associated with an increased risk of developing affective disorders and chronic pain conditions. This study examined the effect of maternal deprivation (MD) on nociceptive responding prior to and following peripheral nerve injury (L5-L6 spinal nerve ligation [SNL]). Because neuroimmune signaling plays an important role in pain and affective disorders, associated alterations in glial and cytokine expression were assessed in key brain regions associated with emotional and nociceptive responding, the hippocampus and prefrontal cortex. MD female, but not male, rats exhibited thermal hypoalgesia and mechanical allodynia compared with control (non-MD) counterparts. SNL resulted in mechanical and cold allodynia in MD and control rats of both sexes. However, MD females exhibited enhanced SNL-induced allodynic responding compared with non-MD counterparts. Interleukin 6 (IL-6) expression was reduced in the prefrontal cortex of MD-SNL males when compared with non-SNL counterparts. Glial fibrillary acidic protein and IL-1β expression in the hippocampus of MD-SNL males was increased compared with non-MD controls. MD-SNL females exhibited reduced tumor necrosis factor alpha in the prefrontal cortex with a concomitant increase in IL-6 and tumor necrosis factor alpha expression in the hippocampus, compared with either MD or SNL alone. In conclusion, MD female, but not male, rats exhibit enhanced nociceptive responding following peripheral nerve injury, effects that may relate to the distinct neuroinflammatory profile observed in female versus male rats. ⋯ This study demonstrates that females rats exposed to early-life stress exhibit enhanced neuropathic pain responding, effects that are associated with alterations in neuroinflammatory mediators. Increased understanding of the interactions among early-life stress, gender, and pain may lead to the identification of novel therapeutic targets for the treatment of chronic pain disorders.
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Many pain syndromes are associated with abnormal proliferation of peripheral sensory fibers. We showed previously that angiotensin II, acting through its type 2 receptor (AT2), stimulates axon outgrowth by cultured dorsal root ganglion neurons. In this study, we assessed whether AT2 mediates nociceptor hyperinnervation in the rodent hind paw model of inflammatory pain. Plantar injection of complete Freund's adjuvant (CFA), but not saline, produced marked thermal and mechanical hypersensitivity through 7 days. This was accompanied by proliferation of dermal and epidermal PGP9.5-immunoreactive (ir) and calcitonin gene-related peptide-immunoreactive (CGRP-ir) axons, and dermal axons immunoreactive for GFRα2 but not tyrosine hydroxylase or neurofilament H. Continuous infusion of the AT2 antagonist PD123319 beginning with CFA injection completely prevented hyperinnervation as well as hypersensitivity over a 7-day period. A single PD123319 injection 7 days after CFA also reversed thermal hypersensitivity and partially reversed mechanical hypersensitivity 3 hours later, without affecting cutaneous innervation. Angiotensin II-synthesizing proteins renin and angiotensinogen were largely absent after saline but abundant in T cells and macrophages in CFA-injected paws with or without PD123319. Thus, emigrant cells at the site of inflammation apparently establish a renin-angiotensin system, and AT2 activation elicits nociceptor sprouting and heightened thermal and mechanical sensitivity. ⋯ Short-term AT2 activation is a potent contributor to thermal hypersensitivity, whereas long-term effects (such as hyperinnervation) also contribute to mechanical hypersensitivity. Pharmacologic blockade of AT2 signaling represents a potential therapeutic strategy aimed at biologic mechanisms underlying chronic inflammatory pain.
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The effect of long-term administration of imipramine, a tricyclic antidepressant, on the phosphorylation status of cyclic adenosine monophosphate-responsive element-binding protein (CREB), mitogen-activated protein kinase family members, and phospholipase γ-1 (PLCγ-1) was investigated in the dorsal horn of the spinal cord following peripheral nerve lesion. Nerve injury induced an ipsilateral long-lasting increased phosphorylation of CREB and PLCγ-1 but not extracellular signal-regulated kinase (ERK1,2), p38, and c-Jun N-terminal kinase. Daily administration of imipramine (5, 10, or 30 mg/kg) for 21 days progressively reduced both tactile-induced neuropathic pain hypersensitivity and thermal hyperalgesia. After withdrawal of treatment, the antinociceptive effect of imipramine was gradually abolished but still remained for at least 3 weeks. Conversely, no analgesic effect was observed with short-term imipramine treatment. Moreover, imipramine therapy reversed nerve injury-induced CREB and PLCγ-1 phosphorylation but had no effect on ERK1,2, p38, and c-Jun N-terminal kinase activity. These results indicate that long-term administration of imipramine may prevent some of the harmful changes in the spinal cord dorsal horn following nerve injury. However, imipramine analgesic effect takes time to develop and mature, which might explain in part why the clinical analgesic effect of tricyclic antidepressants develops with a delay after the beginning of treatment. Our data also provide evidence that prolonged imipramine treatment may induce antinociception in neuropathic pain conditions because of its action on the PLCγ-1/CREB-signaling pathway. ⋯ This article demonstrates that long-term treatment with imipramine reverses some of the marked effects induced by peripheral nerve injury in the spinal dorsal horn that contribute to long-term maintenance of sensory disorder, providing a new view to the mechanisms of action of these drugs.