Articles: hyperalgesia.
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Chronic use of opioid is associated with pro-nociceptive phenomena such as hyperalgesia or tolerance. The interaction between opioid and non-steroidal anti-inflammatory drugs (NSAIDs) with respect to opioid-associated hyperalgesia and tolerance remains largely unknown. This study examines the effect of subcutaneous or intrathecal administration of ketorolac, an NSAID, on recurrent withdrawal induced hyperalgesia and tolerance to spinal morphine in rats. ⋯ Compared to controls, all morphine infused animals showed similar changes in their dose responses to spinal morphine, effective dose 50 values and tolerance ratios; and these changes were not affected by the ketorolac given subcutaneously. The effect of ketorolac on tolerance was further examined by directly delivering ketorolac to the spinal cord, and again we observed similar changes in the daily latency, percentage of area under the curve and percentage of maximal possible effects among groups infused with morphine, regardless of intrathecal ketorolac treatment. Together, our results demonstrate that recurrent withdrawal is associated with hyperalgesia but this has no effect on the tolerance development; ketorolac protects against recurrent withdrawal induced hyperalgesia without significantly altering spinal morphine tolerance.
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Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. ⋯ Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.
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Randomized Controlled Trial Comparative Study
Placebo-controlled comparison of a morphine/dextromethorphan combination with morphine on experimental pain and hyperalgesia in healthy volunteers.
In this double-blind, placebo-controlled, crossover study we compared the analgesic effect of a single oral dose of 30-mg dextromethorphan and 30-mg morphine combination (MS/DM) to 30 mg morphine (MS) alone and either placebo or 30 mg dextromethorphan (DM) on cutaneous sensitization induced by heat/capsaicin (topical) sensitization on the forearm and the brief thermal sensitization model on the thigh in 22 healthy volunteers. Outcome measures were areas of secondary hyperalgesia to brush and von Frey hair stimulation in both sensitization models and the painfulness of acute thermal noxious stimulation on the upper arm. Compared with placebo, both MS/DM and morphine had some effect on the secondary hyperalgesia and reduced the painfulness of a noxious thermal stimulus. The analgesic effect of MS/DM was not superior to that of morphine on any outcome measure. These results differ from preclinical studies with animal experimental pain models in which DM markedly potentiated the analgesic effects of opioids, but they are in accordance with recent clinical trials for chronic pain. ⋯ Adding dextromethorphan to morphine (1:1 ratio) did not enhance analgesia on measures of experimental cutaneous sensitization and acute noxious thermal stimulation in healthy volunteers. The results differ from preclinical studies but agree with clinical trials. Human experimental models of pain and neuronal sensitization, which are responsive to oral opioids, allow efficient study of opioid combination analgesics and simplify the process for determining the optimal dose and/or dose ratio.
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Disinhibition of neurons in the superficial spinal dorsal horn, via microglia - neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain. ⋯ The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.
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The relief of neuropathic pain after spinal cord injury (SCI) remains daunting, because pharmacologic intervention works incompletely and is accompanied by multiple side effects. Transplantation of human cells that make specific biologic agents that can potentially modulate the sensory responses that are painful would be very useful to treat problems such as pain. To address this need for clinically useful human cells, the human neuronal NT2 cell line was used as a source to isolate a unique human neuronal cell line that synthesizes and secretes/releases the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and glycine. This new cell line, hNT2.17, expresses an exclusively neuronal phenotype, does not incorporate bromodeoxyuridine during differentiation, and does not express the tumor-related proteins fibroblast growth factor 4 and transforming growth factor-alpha during differentiation after 2 weeks of treatment with retinoic acid and mitotic inhibitors. The transplant of predifferentiated hNT2.17 cells was used in the excitotoxic SCI pain model, after intraspinal injection of the mixed AMPA/metabotropic receptor agonist quisqualic acid (QUIS). When hNT2.17 cells were transplanted into the lumbar subarachnoid space, tactile allodynia and thermal hyperalgesia induced by the injury were quickly and potently reversed. Control cell transplants of nonviable hNT2.17 cells had no effect on the hypersensitivity induced by QUIS. The effects of hNT2.17 cell grafts appeared 1 week after transplants and did not diminish during the 8-week course of the experiment when grafts were placed 2 weeks after SCI. Immunohistochemistry and quantification of the human grafts were used to ensure that many grafted cells were still present and synthesizing GABA at the end of the study. These data suggest that the human neuronal hNT2.17 cells can be used as a "biologic minipump" for antinociception in models of SCI and neuropathic pain. ⋯ This study describes the initial characterization and use of a human-derived cell line to treat neuropathic pain that would be suitable for clinical application, once further tested for safety and approved by the Food and Drug Administration. A dose of these human cells could be delivered with a spinal tap and affect the intrathecal spinal environment for sensory system modulation.