Articles: hyperalgesia.
-
Comparative Study
Chronic inflammatory pain is associated with increased excitability and hyperpolarization-activated current (Ih) in C- but not Aδ-nociceptors.
Inflammatory pain hypersensitivity results partly from hyperexcitability of nociceptive (damage-sensing) dorsal root ganglion (DRG) neurons innervating inflamed tissue. However, most of the evidence for this is derived from experiments using acute inflammatory states. Herein, we used several approaches to examine the impact of chronic or persistent inflammation on the excitability of nociceptive DRG neurons and on their expression of I(h) and the underlying hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which regulate neuronal excitability. ⋯ This included an afterdischarge response to noxious pinch, which may contribute to inflammatory mechanohyperalgesia, and increased incidence of spontaneous activity (SA) and decreased electrical thresholds, which are likely to contribute to spontaneous pain and nociceptor sensitization, respectively. We also show, using voltage clamp in vivo, immunohistochemistry and behavioral assays that (1) the inflammation-induced nociceptor hyperexcitability is associated, in C- but not Aδ-nociceptors, with increases in the mean I(h) amplitude/density and in the proportion of I(h) expressing neurons, (2) increased proportion of small DRG neurons (mainly IB4-negative) expressing HCN2 but not HCN1 or HCN3 channel protein, (3) increased HCN2- immunoreactivity in the spinal dorsal horn, and (4) attenuation of inflammatory mechanoallodynia with the selective I(h) antagonist, ZD7288. Taken together, the findings suggest that C- but not Aδ-nociceptors sustain chronic inflammatory pain and that I(h)/HCN2 channels contribute to inflammation-induced C-nociceptor hyperexcitability.
-
Perceived control over pain can attenuate pain perception by mechanisms of endogenous pain control and emotional reappraisal irrespective of whether this control is exerted or only perceived. Self-initiated termination of pain elicits different expectations of subsequent pain relief as compared to perceived pain control. It is unknown whether and how this perceived vs. exerted control on pain differs and affects subsequent pain relief. ⋯ Using controllability as factor, there was dissociable neural activity during pain relief: following the perceived control condition neural activity was found in the orbitofrontal and mediofrontal cortex and, following the exerted control condition, in the anterolateral and dorsolateral prefrontal cortex and posterior parietal cortex. We conclude that (i) pain controllability has an impact on pain relief and (ii) the prefrontal cortex shows dissociable neural activity during pain relief following exerted vs. perceived pain control. This might reflect the higher grade of uncertainty during pain relief following perceived pain control mediated by the orbitofrontal and medial prefrontal cortex and processes of working memory and updating expectations during pain relief following exerted control mediated by the lateral prefrontal cortex.
-
Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical for neuronal plasticity. However, how it participates in central sensitization underlying chronic pain is unclear. Here, we show that NMDA receptors are required for the functional role of spinal cord mTOR in bone cancer pain induced by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, a specific mTOR inhibitor, dose dependently attenuated the development and maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. Rapamycin alone did not affect locomotor activity and acute responses to thermal or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) was increased time dependently in L(4-5) dorsal horn and transiently in L(4-5) dorsal root ganglions on the ipsilateral side after PCC injection, although total expression of mTOR or p70S6K was not changed in these regions. The increases in dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn activation of the mTOR pathway participates in NMDA receptor-triggered dorsal central sensitization under cancer pain conditions. ⋯ The present study shows that inhibition of spinal mTOR blocks cancer-related pain without affecting acute pain and locomotor function. Given that mTOR inhibitors are FDA-approved drugs, mTOR in spinal cord may represent a potential new target for preventing and/or treating cancer-related pain.
-
Experimental neurology · Apr 2012
Prostaglandin E2 contributes to the synthesis of brain-derived neurotrophic factor in primary sensory neuron in ganglion explant cultures and in a neuropathic pain model.
Brain-derived neurotrophic factor (BDNF) exists in small to medium size neurons in adult rat dorsal root ganglion (DRG) and serves as a modulator at the first synapse of the pain transmission pathway in the spinal dorsal horn. Peripheral nerve injury increases BDNF expression in DRG neurons, an event involved in the genesis of neuropathic pain. In the present study, we tested the hypothesis that prostaglandin E2 (PGE2) over-produced in injured nerves contributes to the up-regulation of BDNF in DRG neurons. ⋯ Taken together, EP1 and EP4 receptor subtypes, PKA, ERK/MAPK and CREB signaling pathways as well as NGF are involved in PGE2-induced BDNF synthesis in DRG neurons. Injured nerve derived-PGE2 contributes to BDNF up-regulation in DRG neurons following nerve injury. Facilitating the synthesis of BDNF in primary sensory neurons is a novel mechanism underlying the role of PGE2 in the genesis of neuropathic pain.
-
Visceral hyperalgesia is a multifactorial gastrointestinal disorder which featured with alterations of abdominal motility and/or gut sensitivity, and is believed to be triggered by environmental stressor or psychological factors. However, its etiology remains incompletely understood. In this study, we aimed to investigate whether nerve growth factor (NGF)-mediated neuronal plasticity is involved in neonatal maternal separation (NMS)-induced visceral hypersensitivity in adult rats, and whether NGF antagonist can attenuate or block such development. ⋯ Further, as intra-peritoneal administration of NGF (10 μl at 1 μg/kg/day) was given to NH rats during neonatal period, effects that comparable to NMS induction were observed in the adulthood. In contrast, when NMS rats were treated with NGF antagonist K252a (10 μl/day from postnatal days 2-14), which acts against tyrosine kinases, the neonatal stress-induced down-shifted visceral pain threshold was restored and neuronal activation, specifically NGF and neuropeptide production, was attenuated. In conclusion, our data strongly suggest that NGF triggers neuronal plasticity and plays a crucial role in NMS-induced visceral hypersensitivity in which NGF antagonism provides positive inhibition via blocking the tyrosine phosphorylation of TrkA.