Neuroscience
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Although skeletal pain plays a major role in reducing the quality of life in patients suffering from osteoarthritis, Paget's disease, sickle cell anemia and bone cancer, little is known about the mechanisms that generate and maintain this pain. To define the peripheral fibers involved in transmitting and modulating skeletal pain, we used immunohistochemistry with antigen retrieval, confocal microscopy and three-dimensional image reconstruction of the bone to examine the sensory and sympathetic innervation of mineralized bone, bone marrow and periosteum of the normal mouse femur. Thinly myelinated and unmyelinated peptidergic sensory fibers were labeled with antibodies raised against calcitonin gene-related peptide (CGRP) and the unmyelinated, non-peptidergic sensory fibers were labeled with the isolectin B4 (Bandeira simplicifolia). ⋯ CGRP, RT-97, and tyrosine hydroxylase immunoreactive fibers, but not isolectin B4 positive fibers, were present throughout the bone marrow, mineralized bone and the periosteum. While the periosteum is the most densely innervated tissue, when the total volume of each tissue is considered, the bone marrow receives the greatest total number of sensory and sympathetic fibers followed by mineralized bone and then periosteum. Understanding the sensory and sympathetic innervation of bone should provide a better understanding of the mechanisms that drive bone pain and aid in developing therapeutic strategies for treating skeletal pain.
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In the present three-part study, the effects of intrathecally administered N-methyl-D-aspartate (NMDA) receptor antagonists on responses to noxious and innocuous colorectal distention (CRD) were examined. In the first part, a passive-avoidance paradigm was used to confirm that 80 mm Hg CRD is a noxious stimulus since it produced avoidance behavior. Acquisition of this behavior was blocked by the NMDA receptor antagonist D(-)-2-amino-5-phosphonopetanoic acid (APV, 60 nmol, intrathecal). ⋯ The magnitude of attenuation was similar for both stimulus paradigms. These data expand upon our previous dorsal horn neuronal recordings which showed that spinal NMDA receptors partially mediate the processing of both noxious and innocuous colorectal stimuli. They further underscore a difference from somatic tissue in the role of NMDA receptors in processing acute or transient visceral stimuli in the absence of tissue injury.
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One of us showed previously [Cuajungco and Lees (1998) Brain Res. 799, 188-129] that nitric oxide injected into the cerebrum in vivo causes zinc staining to appear in the somata of neurons and suggested that this staining of somata might be accompanied by a depletion (release) of zinc from axon terminals. In the present study, we confirm earlier results and report that there is a dramatic loss (apparent release) of histologically reactive zinc from the boutons of zinc-containing axons induced by infusion of nitric oxide into the brain in vivo. Rats were anesthetized with halothane and a cannula was inserted into the hippocampus. ⋯ Two hours after infusion, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining for zinc in the brains revealed that sperminenitric oxide, but not control (spermine only) produced up to 95% depletion of zinc staining from the zinc-containing boutons. TSQ-positive neurons were also conspicuous throughout injection sites, in both the cerebral cortex and in the cerebellar cortex, where the Purkinje neurons were especially vivid, despite the scarcity of zinc-containing axonal boutons. It is suggested that the TSQ-stainable zinc in somata might represent intracellular stores mobilized from within or permeating extracellular stores.
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In the present study we investigated the effects of spinal morphine on the electrically and naturally evoked responses of gracile nuclei neurones in a rat model of neuropathy, induced by the tight ligation of lumbar L5/6 spinal nerves. Two weeks after surgery, animals were prepared for electrophysiological recordings and neuronal responses were characterised to a range of controlled natural (brush, low- and high-intensity von Frey filaments, heat 45 degrees C) and peripheral electrical stimuli. Morphine (0.1, 0.25, 1 and 5 microg) was applied spinally and its effect was compared to that in sham-operated or naive animals. ⋯ In complete contrast, morphine produced a marked inhibition of the low-intensity punctate mechanical evoked responses (von Freys 2 and 9 g) after nerve injury, an effect that was totally lacking in the sham-operated or naive animal groups. This dramatic shift was selective for the low-intensity punctate mechanical stimuli and such an effect was not seen with the noxious mechanical punctate stimulus (von Frey 75 g) where there was a modest inhibition in all groups. Our results suggest that there is plasticity in the opioid modulation of dorsal column projection pathways following spinal nerve ligation and these alterations appear to interact with sensory pathways conveying low-threshold punctate stimuli.
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The purpose of the present study was to investigate the role of mu-opioid receptor in inflammatory hyperalgesia in intact and in spinalized animals and the interaction between mu-opioid and alpha2-adrenergic receptor in acute pain and inflammatory hyperalgesia. Behavioral responses to mechanical and heat stimuli were studied in mu-opioid receptor knockout mice and wildtype control mice. Thermal nociception was evaluated by measuring paw withdrawal latencies to radiant heat applied to the hindpaws. ⋯ Our observations indicate that the mu-opioid receptors do not play an important role in alpha2-adrenergic receptor agonist-mediated acute antinociception. In addition, micro-opioid receptors are not tonically involved in the modulation of inflammation-induced mechanical and thermal hyperalgesia, and the supraspinal control of spinal reflexes. However, in the presence of inflammation, mu-opioid receptors play an important role in the antihyperalgesic actions of an alpha2-adrenergic receptor agonist.