Brain, behavior, and immunity
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Brain Behav. Immun. · Jan 2009
G protein-coupled receptor kinase 6 controls post-inflammatory visceral hyperalgesia.
Post-inflammatory pain is a poorly understood phenomenon. G protein-coupled receptors are involved in regulating pain signaling in the context of inflammation. G protein-coupled receptor kinases (GRK) modulate signaling through these receptors. ⋯ Furthermore, in vitro IL-1beta sensitized the capsaicin receptor TRPV1 and this process was inhibited by over-expression of GRK6. We describe the novel concept that GRK6 inhibits post-inflammatory visceral hyperalgesia but does not contribute to visceral pain in naive animals. We propose that GRK6 regulates inflammation-induced sensitization of TRPV1.
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Brain Behav. Immun. · Jan 2009
Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome.
Complex regional pain syndrome (CRPS) is a chronic pain condition that usually arises from an injury or as a complication from a surgical procedure. CRPS can result from multiple mechanisms including active processes involving both the peripheral and the central nervous system and sickness like responses involving interactions between the immune and nervous systems. In animal models both peripheral and central sensitization as well as loss of inhibition has been implicated in neuropathic pain states. ⋯ Using immunohistochemical techniques, this study evaluated the degree of astrocytic and microglial activation as well as neuronal loss in autopsy tissue from the cervical, thoracic and lumbar spinal cord of a patient afflicted with CRPS as compared to four control individuals. The major findings of this study are that in long standing CRPS there was significant posterior horn cell loss and activation of both microglia and astrocytes most prominently at the level of the original injury but extending throughout the entire length of the spinal cord. Our hope is that the data obtained from this and other studies of autopsy material may aid in elucidating the mechanisms involved in the pathophysiology of CRPS, which may lead to the refinement of current therapies as well as novel treatments.
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Brain Behav. Immun. · Jan 2009
Attenuation of morphine tolerance by minocycline and pentoxifylline in naive and neuropathic mice.
We have previously demonstrated that glial inhibitors reduce the development of allodynia and hyperalgesia, potentiating the effect of a single morphine dose in a neuropathic pain model. This study explores the effects of two glial activation inhibitors, minocycline and pentoxifylline, on the development of tolerance to morphine in naive and chronic constriction injury (CCI)-exposed mice. Administration of morphine to naive (20 mg/kg; i.p.) and CCI-exposed mice (40 mg/kg; i.p.) twice daily resulted in tolerance to its anti-nociceptive effect after 6 days. ⋯ Western blot analysis of CD11b/c and GFAP protein demonstrated that minocycline and pentoxifylline, at doses delaying development of tolerance to morphine analgesia, significantly diminished the morphine-induced increase in CD11b/c protein level. We found that repeated systemic administration of glial inhibitors significantly delays development of morphine tolerance by attenuating the level of this microglial marker under normal and neuropathic pain conditions. Our results support the idea that targeting microglial activation during morphine therapy/treatment is a novel and clinically promising method for enhancing morphine's analgesic effects, especially in neuropathic pain.
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Brain Behav. Immun. · Nov 2008
Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia.
Spinal proinflammatory cytokines are powerful pain-enhancing signals that contribute to pain following peripheral nerve injury (neuropathic pain). Recently, one proinflammatory cytokine, interleukin-1, was also implicated in the loss of analgesia upon repeated morphine exposure (tolerance). In contrast to prior literature, we demonstrate that the action of several spinal proinflammatory cytokines oppose systemic and intrathecal opioid analgesia, causing reduced pain suppression. ⋯ Statistical analysis demonstrated that a cluster of cytokines and chemokines was linked with pain-related behavioral changes. Moreover, blockade of spinal proinflammatory cytokines during a stringent morphine regimen previously associated with altered neuronal function also attenuated enhanced pain, supportive that proinflammatory cytokines are importantly involved in tolerance induced by such regimens. These data implicate multiple opioid-induced spinal proinflammatory cytokines in opposing both acute and chronic opioid analgesia, and provide a novel mechanism for the opposition of acute opioid analgesia.
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Brain Behav. Immun. · Oct 2008
Contribution of activated interleukin receptors in trigeminal ganglion neurons to hyperalgesia via satellite glial interleukin-1beta paracrine mechanism.
The present study investigated whether under in vivo conditions, inflammation alters the excitability of nociceptive Adelta-trigeminal ganglion (TRG) neurons innervating the facial skin via a cytokine paracrine mechanism. We used extracellular electrophysiological recording with multibarrel-electrodes in this study, and complete Freund's adjuvant (CFA) was injected into the rat facial skin. The threshold for escape from mechanical stimulation applied to the whisker pad area in inflamed rats (2 days after CFA injection) was significantly lower than that in control rats. ⋯ The mechanical threshold of nociceptive-TRG neurons in inflamed rats was significantly lower than that in control rats, but was not significantly different between control and inflamed rats after application of an IL-1ra. These results suggested that inflammation modulates the excitability of nociceptive Adelta-TRG neurons innervating the facial skin via IL-1beta paracrine action within trigeminal ganglia. Such an IL-1beta release could be important in determining trigeminal inflammatory hyperalgesia.