Brain, behavior, and immunity
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Brain Behav. Immun. · Jul 2007
Comparative StudyInterleukin-1 signaling modulates stress-induced analgesia.
Exposure to stressful stimuli is often accompanied by reduced pain sensitivity, termed "stress-induced analgesia" (SIA). In the present study, the hypothesis that interleukin-1 (IL-1) may play a modulatory role in SIA was examined. Two genetic mouse models impaired in IL-1-signaling and their wild-type (WT) controls were employed. ⋯ Interestingly, the analgesic response to moderate stress was markedly potentiated in the mutant strains, as compared with their WT controls. The present results support our previous findings that in the absence of IL-1, stress response to mild stress is noticeably diminished. However, the analgesic response to moderate stress is markedly potentiated in mice with impaired IL-1 signaling, corroborating the anti-analgesic role of IL-1 in several pain modulatory conditions, including SIA.
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Brain Behav. Immun. · Jul 2007
Age-related changes in the spinal cord microglial and astrocytic response profile to nerve injury.
Neuropathic pain, arising from nerve injury or secondary to other diseases, occurs in young children as well as adults but little is known about its postnatal development. Neonatal rat pups do not display mechanical allodynia following nerve injury and young rats recover faster from spinal nerve damage. Since both spinal microglia and astrocytes are strongly implicated in the maintenance of persistent pain, we hypothesized that the magnitude and time course of spinal cord glial activation following nerve injury change throughout postnatal development. ⋯ We show that in the adult SNI evokes clear dorsal horn microglial activation at 5 days and astrocytic activation at 7 days post surgery. In contrast, SNI in young animals evokes a weak microglial response but a robust astrocytic response with an early onset at day 1 that is not observed in adults, followed by a second activation at day 7. These results highlight the differential development of the glial response to nerve injury which may explain the lack of neuropathic allodynia in young animals.
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Brain Behav. Immun. · Jul 2007
Interleukin-6 mediates low-threshold mechanical allodynia induced by intrathecal HIV-1 envelope glycoprotein gp120.
Spinal cord glia (microglia and astrocytes) contribute to enhanced pain states. One model that has been used to study this phenomenon is intrathecal (i.t.) administration of gp120, an envelope glycoprotein of HIV-1 known to activate spinal cord glia and thereby induce low-threshold mechanical allodynia, a pain symptom where normally innocuous (non-painful) stimuli are perceived as painful. Previous studies have shown that i.t. gp120-induced allodynia is mediated via the release of the glial pro-inflammatory cytokines, tumor necrosis factor-alpha (TNF), and interleukin-1beta (IL-1). ⋯ This IL-6 blockade abolished gp120-induced mechanical allodynia. While the literature predominantly documents the cascade of pro-inflammatory cytokines as beginning with TNF, followed by the stimulation of IL-1, and finally TNF plus IL-1 stimulating the release of IL-6, the present findings indicate that a blockade of IL-6 inhibits the gp120-induced elevations of TNF, IL-1, and IL-6 mRNA in dorsal spinal cord, elevation of IL-1 protein in lumbar dorsal spinal cord, and TNF and IL-1 protein release into the surrounding lumbosacral cerebrospinal fluid. These results would suggest that IL-6 induces pain facilitation, and may do so in part by stimulating the production and release of other pro-inflammatory cytokines.
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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
CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy.
Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2',3'-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. ⋯ Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.