The journal of pain : official journal of the American Pain Society
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In this study, effects of chronic pain and pain-related fear on orienting and maintenance of attention toward pain stimuli were evaluated by tracking eye movements within a dot-probe paradigm. The sample comprised matched chronic pain (n = 24) and pain-free (n = 24) groups, each of which included lower and higher fear of pain subgroups. Participants completed a dot-probe task wherein eye movements were assessed during the presentation of sensory pain-neutral, health catastrophe-neutral, and neutral-neutral word pairs. Higher fear of pain levels were associated with biases in 1) directing initial gaze toward health catastrophe words and, among participants with chronic pain, 2) subsequent avoidance of threat as reflected by shorter first fixation durations on health catastrophe words compared to pain-free cohorts. As stimulus word pairs persisted for 2,000 ms, no group differences were observed for overall gaze durations or reaction times to probes that followed. In sum, this research identified specific biases in visual attention related to fear of pain and chronic pain during early stages of information processing that were not evident on the basis of later behavior responses to probes. ⋯ Effects of chronic pain and fear of pain on attention were examined by tracking eye movements within a dot-probe paradigm. Heightened fear of pain corresponded to biases in initial gaze toward health catastrophe words and, among participants with chronic pain, subsequent gaze shifts away from these words. No reaction time differences emerged.
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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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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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Crossing the hands over the body midline reduces the perceived intensity of nociceptive stimuli applied to the hands by impairing the ability to localize somatosensory stimuli. The neural basis of this "crossed-hands analgesia" has not been investigated previously, although it has been proposed that the effect may be modulated by multimodal areas. We used functional magnetic resonance imaging to test the hypothesis that crossed-hands analgesia is mediated by higher-order multimodal areas rather than by specific somatosensory ones. Participants lay in the scanner while mechanical painful stimuli were applied to their hands held in either a crossed or uncrossed position. They reported significantly lower perceived intensity of pain when their hands were crossed. Although activations elicited by stimuli applied to the crossed hands revealed significantly greater blood oxygen level-dependent responses in the anterior cingulate cortex, the insula, and the medial frontal gyrus, the blood oxygen level-dependent responses in the superior parietal lobe were greater with the hands uncrossed. Our results provide evidence that crossed-hands analgesia is mediated by higher-order frontoparietal multimodal areas involved in sustaining and updating body and spatial representations. ⋯ We found crossed-hands analgesia to be mediated by multimodal areas, such as the posterior parietal, cingulate, and insular cortices, implicated in space and body representation. Our findings highlight how the perceived intensity of painful stimuli is shaped by how we represent our body and the space surrounding it.