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.
"Tissue inflammation sensitizes and increases excitability of primary afferent neurons causing an upregulation of MOP, KOP, DOP and NOP on the primary afferent nerve fiber terminals and the non-neuronal cells like lymphocytes (Chen and Sommer 2006; Stein and Lang 2009). Hence, opioids can directly reduce peripheral afferent nociceptive signals (Sawynok 2003; Stein et al. 2009). Inflammation in the periphery also causes spinal neuroplasticity such as the activation of glia, which in turn enhance pain by releasing proinflammatory mediators (Raghavendra et al. 2004; Watkins and Maier 2003). "
[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.
"Finally, Gi-mediated inhibition constitutes an important checkpoint in determining nociceptor excitability. The anti-nociceptive actions of cannabinoids and opioids, which bind to GPCRs, are also mediated via peripheral mechanisms (Agarwal et al., 2007; Kinsey et al., 2009; Lever et al., 2009; Stein and Lang, 2009). "
[Show abstract][Hide abstract] ABSTRACT: There are two basic categories of pain: physiological pain, which serves an important protective function, and pathological pain, which can have a major negative impact on quality of life in the context of human disease. Major progress has been made in understanding the molecular mechanisms that drive sensory transduction, amplification and conduction in peripheral pain-sensing neurons, communication of sensory inputs to spinal second-order neurons, and the eventual modulation of sensory signals by spinal and descending circuits. This poster article endeavors to provide an overview of how molecular and cellular mechanisms underlying nociception in a physiological context undergo plasticity in pathophysiological states, leading to pain hypersensitivity and chronic pain.
"Accordingly, our studies aimed at assessing the potency/efficacy of tapentadol, compared with reboxetine , a selective NA reuptake inhibitor with antidepressant potentialities (Wong et al., 2000), and morphine (a preferential m-opioid receptor agonist; Dhawan et al., 1996) alone or in combination, to alleviate hyperalgesia/allodynia in CCI-ION versus CCI-SN rats. In addition, because previous studies showed that both opioids (Jessop, 2006; Stein and Lang, 2009) and antidepressants (Kenis and Maes, 2002; Hashioka, 2011) have anti-inflammatory effects, we investigated whether tapentadol, with such dual pharmacological properties, could affect neuropathic pain-associated overexpression of neuroinflammatory markers in ganglia and central tissues in CCI-SN and CCI-ION rats (Latrémolière et al., 2008). "
[Show abstract][Hide abstract] 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.
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.
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.
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 · 2.93 Impact Factor
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