Brain, behavior, and immunity
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Brain Behav. Immun. · Jul 2007
Stereological and somatotopic analysis of the spinal microglial response to peripheral nerve injury.
The involvement of glia, and glia-neuronal signalling in enhancing nociceptive transmission has become an area of intense scientific interest. In particular, a role has emerged for activated microglia in the development and maintenance of neuropathic pain following peripheral nerve injury. Following activation, spinal microglia proliferate and release many substances which are capable of modulating neuronal excitability within the spinal cord. ⋯ Following SNI the number of microglia was 82,034+/-8828. While the pattern of microglial activation generally followed somatotopic boundaries, with the majority of microglia within the territory occupied by peripherally axotomised primary afferents, some spread was seen into regions occupied by intact, 'spared' central projections of the sural nerve. This study provides a reproducible method of assaying spinal microglial dynamics following peripheral nerve injury both quantitatively and spatially.
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Brain Behav. Immun. · Jul 2007
A novel immune-to-CNS communication pathway: cells of the meninges surrounding the spinal cord CSF space produce proinflammatory cytokines in response to an inflammatory stimulus.
Pain is enhanced in response to elevations of proinflammatory cytokines in spinal cerebrospinal fluid (CSF), following either intrathecal injection of these cytokines or intrathecal immune challenge with HIV-1 gp120 that induces cytokine release. Spinal cord glia have been assumed to be the source of endogenous proinflammatory cytokines that enhance pain. However, assuming that spinal cord glia are the sole source of CSF cytokines may be an underestimate, as the cellular composition of the meninges surrounding the spinal cord CSF space includes several cell types known to produce proinflammatory cytokines. ⋯ In addition, stimulation of isolated meninges in vitro with gp120 induced the release of TNF-alpha and IL-1beta, indicating that the resident cells of the meninges are able to respond without immune cell recruitment. Taken together, these data document that the meninges are responsive to immunogenic stimuli in the CSF and that the meninges may be a source of immune products detected in CSF. The ability of the meninges to release to proinflammatory signals suggests a potential role in the modulation of pain.
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Brain Behav. Immun. · Jul 2007
Involvement of glia in central sensitization in trigeminal subnucleus caudalis (medullary dorsal horn).
Central sensitization is a crucial mechanism underlying the increased excitability of nociceptive pathways following peripheral tissue injury and inflammation. We have previously demonstrated that the small-fiber excitant and inflammatory irritant mustard oil (MO) applied to the tooth pulp produces glutamatergic- and purinergic-dependent central sensitization in brainstem nociceptive neurons of trigeminal subnucleus caudalis (Vc). Recent studies have implicated both astrocytes and microglia in spinal nociceptive mechanisms, showing, for example, that inhibition of spinal astroglial metabolism or spinal microglial p38MAPK activation can attenuate hyperalgesia in inflammatory pain models but have not tested effects of glial inhibitors on central sensitization in functionally identified spinal nociceptive neurons. ⋯ The i.t. application of SB or FA markedly attenuated the MO-induced increases in pinch RF size and responses to noxious stimuli and the decrease in activation threshold. Neither SB nor FA application significantly affected the baseline (i.e., pre-MO application) RF and response properties. These results suggest that glial metabolic processes are important in the development of Vc central sensitization.
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Brain Behav. Immun. · Jul 2007
Comparative Study Clinical TrialInfluence of pain treatment by epidural fentanyl and bupivacaine on homing of opioid-containing leukocytes to surgical wounds.
Endogenous opioids released from leukocytes extravasating into injured tissue can interact with peripheral opioid receptors to inhibit nociception. Animal studies have shown that the homing of opioid-producing leukocytes to the injured site is modulated by spinal blockade of noxious input. This study investigated whether epidural analgesia (EDA) influences the migration of beta-endorphin (END) and/or met-enkephalin (ENK)-containing leukocytes into the subcutaneous wound tissue of patients undergoing abdominal surgery. ⋯ Samples of cutanous and subcutanous tissue were taken from the wound site at the beginning, at the end and at various times after surgery, and were examined by immunohistochemistry for the presence of END and ENK. We found that (i) epidural bupivacaine, fentanyl and PCIA provided similar and clinically acceptable postoperative pain relief; (ii) compared to PCIA, epidural bupivacaine or fentanyl did not change the gross inflammatory reaction within the surgical wound; (iii) opioid-containing leukocytes were almost absent in normal subcutaneous tissue but migrated to the inflamed wound tissue in ascending numbers within a few hours, reaching a peak at about 24 h after surgery; (iv) compared to PCIA, EDA resulted in significantly decreased homing of END-containing leukocytes to the injured site at 24 h after surgery; and (v) the magnitude of this decrease was similar regardless of the epidural medication. These findings suggest that nociceptive but not sympathetic neurons are primarily involved in the attraction of opioid-containing leukocytes during early stages of inflammation.
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Brain Behav. Immun. · Jul 2007
Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats.
Paclitaxel is a commonly used cancer chemotherapy drug that frequently causes painful peripheral neuropathies. The mechanisms underlying this dose-limiting side effect are poorly understood. Growing evidence supports that proinflammatory cytokines, such as interleukin-1 (IL-1) and tumor necrosis factor (TNF), released by activated spinal glial cells and within the dorsal root ganglia (DRG) are critical in enhancing pain in various animal models of neuropathic pain. ⋯ Moreover, IL-10 gene therapy resulted in increased IL-10 mRNA levels in lumbar DRG and meninges, measured 2 weeks after initiation of therapy, whereas paclitaxel-induced expression of IL-1, TNF, and CD11b mRNA in lumbar DRG was markedly decreased. Taken together, these data support that paclitaxel-induced neuropathic pain is mediated by proinflammatory cytokines, possibly released by activated immune cells in the DRG. We propose that targeting the production of proinflammatory cytokines by intrathecal IL-10 gene therapy may be a promising therapeutic strategy for the relief of paclitaxel-induced neuropathic pain.