Contribution of opioid peptides and receptors in immune cells to exogenous opioid control of neuropathic pain
Final Report Abstract
Opioids (e.g., morphine) are the strongest painkillers and their consumption has dramatically increased worldwide. The alarming rise in the number of deaths from overdoses of prescription opioids has even exceeded those from cocaine and heroin overuse. Opioids produce analgesia at all levels of the nervous system. However, in contrast to the central nervous system (CNS), the activation of opioid receptors outside the CNS has a potential to be devoid of detrimental effects such as respiratory failure, dependence, addiction and misuse. In these studies we found a new mechanism of opioid-mediated pain inhibition with such potential. We discovered that analgesia can be mediated by opioid receptors in immune cells. Interestingly, in contrast to the conventional action of neuronal opioid receptors, which is based on the inhibition of the release of painenhancing mediators (e.g., substance P, calcitonin gene-related peptide), the activation of leukocyte opioid receptors results in the secretion of pain-inhibiting opioid peptides. Mechanistically, this analgesia is mediated by a well organized intracellular pathways involving Gαi/o–coupled mu-, delta- and kappa-opioid receptors engaging Gβγ protein, phospholipase C, inositol 1,4,5-trisphosphate receptors and intracellular calcium. Importantly, we demonstrated these effects ex vivo and in vivo in a widely accepted animal model of neuropathic pain. Therefore, our findings are of potential clinical relevance and can stimulate the development of new technologies to deliver opioid painkillers to the most important peripheral painful tissue to avoid serious adverse effects produced by conventional opioids, cannabinoids and nonsteroidal antiinflammatory drugs. The project was generally executed as originally planned and the main hypothesis has been confirmed.
Publications
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Modulation of peripheral sensory neurons by the immune system: implications for pain therapy. Pharmacological Reviews, vol. 63. 2011, no. 4, pp. 860-881.
Stein C., Machelska H.
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Distinct roles of exogenous opioid agonists and endogenous opioid peptides in the peripheral control of neuropathy-triggered heat pain. Scientific Reports, 6. 2016: 32799.
Labuz D., Celik M.Ö., Zimmer A., Machelska H.
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Leukocyte opioid receptors mediate analgesia via Ca(2+)-regulated release of opioid peptides. Brain, Behavior, and Immunity, Vol. 57. 2016, pp. 227–242.
Celik M.Ö., Labuz D., Henning K., Busch-Dienstfertig M., Gaveriaux-Ruff C., Kieffer B.L., Zimmer A., Machelska H.
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Opioids and TRPV1 in the peripheral control of neuropathic pain-Defining a target site in the injured nerve. Neuropharmacology,
Vol. 101. 2016, pp. 330–340.
Labuz D, Spahn V, Celik MÖ, Machelska H.
