Peripheral mechanisms of opioid analgesia
ABSTRACT Potent and clinically significant analgesic effects can be brought about by opioids acting outside the central nervous system. Injury and inflammation of peripheral tissues leads to increased synthesis, axonal transport, membrane-directed trafficking and G-protein coupling of opioid receptors in dorsal root ganglion neurons. These events are dependent on neuronal electrical activity, cytokines and nerve growth factor and lead to an enhanced analgesic efficacy of peripherally active opioids. Leukocytes infiltrating inflamed tissue upregulate signal-sequence-encoding mRNA for beta-endorphin and its processing enzymes. Depending on the cell type and stimulus, the opioid release is contingent on extracellular Ca2+ or on release of Ca2+ from endoplasmic reticulum. Analgesia results from inhibition of sensory neuron excitability and of proinflammatory neuropeptide release.
- SourceAvailable from: Mei-Chuan Ko[Show abstract] [Hide abstract]
ABSTRACT: Carrageenan-induced hyperalgesia is a widely used pain model in rodents. However, characteristics of carrageenan-induced hyperalgesia and effects of analgesic drugs under these conditions are unknown in nonhuman primates. The aims of this study were to develop carrageenan-induced hyperalgesia in rhesus monkeys and determine the efficacy and potency of agonists selective for the four opioid receptor subtypes in this model versus acute pain, as compared to non-steroidal anti-inflammatory drugs (NSAIDs). Tail injection of carrageenan produced long-lasting thermal hyperalgesia in monkeys. Systemically administered agonists selective for opioid receptor subtypes, i.e., fentanyl (mu/MOP), U-50488H (kappa/KOP), SNC80 (delta/DOP) and Ro 64-6198 (nociceptin/orphanin FQ/NOP) dose-dependently attenuated carrageenan-induced thermal hyperalgesia with different potencies. In absence of carrageenan, these agonists, except SNC80, blocked acute thermal nociception. Opioid-related ligands, especially Ro 64-6198, were much more potent for their antihyperalgesic than antinociceptive effects. Both effects were mediated by the corresponding receptor mechanisms. Only fentanyl produced scratching at antihyperalgesic and antinociceptive doses consistent with its pruritic effects in humans, illustrating a translational profile of MOP agonists in nonhuman primates. Similar to SNC80, systemically administered NSAIDs ketorolac and naproxen dose-dependently attenuated carrageenan-induced hyperalgesia but not acute nociception. Using two different pain modalities in nonhuman primates, effectiveness of clinically available analgesics like fentanyl, ketorolac and naproxen was distinguished and their efficacies and potencies were compared with the selective KOP, DOP, and NOP agonists. The opioid-related ligands displayed differential pharmacological properties in regulating hyperalgesia and acute nociception in the same subjects. Such preclinical primate models can be used to investigate novel analgesic agents.Psychopharmacology 04/2014; 231(7):1377-1387. DOI:10.1007/s00213-013-3341-0 · 3.99 Impact Factor
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ABSTRACT: BACKGROUND: Convergent data showed that neuropathic pain has specific characteristics at cephalic versus extra-cephalic level, where single-targeted drugs differentially alleviate pain. Because the novel analgesic drug, tapentadol, is acting at two targets, μ-opioid receptors (as agonist) and noradrenaline reuptake (as inhibitor), we tested its effects on neuropathic pain at both cephalic and extra-cephalic levels. METHODS: Sprague-Dawley rats underwent unilateral constriction injury (CCI) to the infraorbital nerve (ION; cephalic territory) or the sciatic nerve (SN; extra-cephalic territory), and alleviation of nerve lesion-induced mechanical allodynia/hyperalgesia was assessed after acute or repeated (for 4 days) treatment with tapentadol compared with morphine and/or reboxetine (noradrenaline reuptake inhibitor) 2 weeks after surgery. Possible changes in the expression of the neuroinflammatory markers activating transcription factor 3 (ATF3), interleukin-6 (IL-6) and brain-derived neurotrophic factor (BDNF) by repeated tapentadol treatment were quantified by real-time reverse transcription polymerase chain reaction in ganglia and central tissues. RESULTS: Acute administration of tapentadol (1-10 mg/kg, i.p.) significantly reduced allodynia in both CCI-SN and CCI-ION rats. Although morphine (3 mg/kg, s.c.) or reboxetine (10 mg/kg, i.p.) alone was only marginally active, the combination of both drugs produced supra-additive effects like those observed with tapentadol. In contrast to repeated morphine whose effects vanished, the anti-allodynic effects of tapentadol remained unchanged after a 4-day treatment. However, the latter treatment with tapentadol did not affect nerve lesion-evoked overexpression of ATF3, IL-6 and BDNF transcripts. CONCLUSIONS: The dual synergistic pharmacological properties of tapentadol, which result in clear-cut anti-neuropathic pain effects at both cephalic and extra-cephalic levels, probably involve mechanisms downstream of nerve injury-induced neuroinflammatory reaction.European journal of pain (London, England) 07/2013; 17(6). DOI:10.1002/j.1532-2149.2012.00259.x · 3.22 Impact Factor
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ABSTRACT: Neuroinflammation in the spinal cord plays a critical role in the processing of inflammatory pain. Docosahexaenoic acid (DHA), a predominant omega-3 polyunsaturated fatty acid in the central nervous system, is known to modulate inflammatory responses in various neurodegenerative disorders. In this study, we investigated whether DHA could reduce inflammatory pain and inhibit neuroinflammation in the spinal cord following carrageenan injection. Intrathecal (i.t.) injection of DHA at 15 min before carrageenan injection blocked carrageenan-induced pain hypersensitivity for more than 6 h. In addition, i.t. injection of DHA at 3 h after carrageenan transiently reversed carrageenan-induced heat hyperalgesia and mechanical allodynia. Furthermore, DHA treatment reduced carrageenan-induced activation of microglia, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and production of proinflammatory cytokines (TNF-α and IL-1β) in the L4-5 spinal cord. In cultured microglial cells, DHA dose-dependently reduced LPS-induced phosphorylation of p38, production of proinflammatory cytokines (TNF-α, IL-1β, IL-6) and chemokines (CCL2, CCL3 and CXCL10). p38 inhibitor SB203580 inhibited LPS-induced expression of proinflammatory cytokines and chemokines in a dose-dependent manner. Taken together, these results provide evidence that DHA has antinociceptive effect in inflammatory pain, which may be attributed to, at least partially, suppressing a microglia-mediated inflammatory response through inhibition of p38 MAPK activation.Neuroscience 03/2013; DOI:10.1016/j.neuroscience.2013.03.003 · 3.33 Impact Factor