Antinociceptive and nociceptive actions of opioids

Departments of Pharmacology, Anesthesiology and Chemistry, University of Arizona, Tucson, Arizona 85724, USA.
Journal of Neurobiology (Impact Factor: 3.84). 10/2004; 61(1):126-48. DOI: 10.1002/neu.20091
Source: PubMed


Although the opioids are the principal treatment options for moderate to severe pain, their use is also associated with the development of tolerance, defined as the progressive need for higher doses to achieve a constant analgesic effect. The mechanisms which underlie this phenomenon remain unclear. Recent studies revealed that cholecystokinin (CCK) is upregulated in the rostral ventromedial medulla (RVM) during persistent opioid exposure. CCK is both antiopioid and pronociceptive, and activates descending pain facilitation mechanisms from the RVM enhancing nociceptive transmission at the spinal cord and promoting hyperalgesia. The neuroplastic changes elicited by opioid exposure reflect adaptive changes to promote increased pain transmission and consequent diminished antinociception (i.e., tolerance).

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Available from: Tamara King, Oct 16, 2014
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    • "Signaling through opioid receptors results in a variety of secondary effects including decreased exocytosis of excitatory amino acids and neuropeptides, and hyperpolarization of post-synaptic neurons leading to decreased transmission of nociceptive signals from the periphery to the dorsal horn of the spinal cord. Opioids also act centrally to limit our awareness of noxious stimuli (Ossipov et al., 2004). Opioid administration results in decreased blood pressure, heart rate, drowsiness, increased smooth muscle tone, and, at high doses sedation and respiratory depression. "
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    • "However, the molecular mechanisms of OIH are largely unknown. Numerous groups have suggested that OIH may be due to tonic, descending facilitation in the spinal cord [4], [5] or in the spinal cord dorsal horn [6], [7] through changes in activity of NMDA receptors. Though neither of these modes of action can be completely ruled out, an alternative OIH mechanism involves functional activation of the innate immune receptor Toll-like receptor 4 (TLR4) known to exhibited by a subpopulation of nociceptive neurons [8], [9]. "
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    • "It is also revealed that cholecystokinin (CCK) is upregulated in the rostral ventromedial medulla (RVM) during persistent opioid exposure. CCK is both antiopioid and pronociceptive via the activation of descending pain facilitation mechanisms from the RVM which enhancing nociceptive transmission at the level of spinal cord and promoting hyperalgesia.42 If it is hypothesized that acute exposure to morphine ultra low dose also arises such descending pain facilitation pathways which needs to be investigated, and if it suppose that this effect is happening at least partially through the spinal cords terminals c-fibers, then c-fibers elimination possibly alleviates the pain facilitating effect of descending pathways induced by morphine ultra low dose treatment. "
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