Induction of pain facilitation by sustained opioid exposure: relationship to opioid antinociceptive tolerance (original) (raw)
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Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure
Biopolymers, 2005
The opioid analgesics, commonly exemplified by morphine, represent the best option for the treatment of severe pain and for the management of chronic pain states, of both malignant and nonmalignant origin. It is well recognized that the prolonged use of opioids is associated with a requirement for ever-increasing doses in order to maintain pain relief at an acceptable and consistent level. This phenomenon is termed analgesic tolerance. While the concept that tolerance can develop as a result of cellular adaptations to the presence of the opioid has been proposed, it is now becoming abundantly clear that tolerance may also be related to a state of hyperalgesia that results from exposure to the opioid itself. Patients who receive long-term opioid therapy sometimes develop unexpected, abnormal pain. Similar paradoxical opioid-induced pain has been confirmed in a number of animal studies, even during the period of continuous opioid delivery. A number of recent studies have demonstrated that such pain may be secondary to neuroplastic changes that occur in the brain and spinal cord. One such change may be the activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM) elicited in part by increased activity of cholecystokinin (CCK) in the RVM. A cascade of pronociceptive events may follow, such as opioid-induced upregulation of spinal dynorphin levels that promotes enhanced input from primary afferent nociceptors. This mechanism appears to depend on intact descending pathways from the RVM, since interrupting this pathway abolishes enhanced abnormal pain. Furthermore, extended opioid exposure also can elicit increased calcitonin gene related peptide (CGRP) and substance P expression in the dorsal root ganglia. It is probable that increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance because the same manipulations that block abnormal pain also block antinociceptive tolerance. Taken together, such studies show that opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin, and enhanced, evoked release of excitatory transmitters from primary afferents. These adaptive changes in response to sustained exposure to opioids indicate the need for the evaluation of the clinical consequences of long-term opioid administration. Additionally, these findings suggest a need for novel chemistry involving design of agents that may counteract opiate-induced neuroplastic adaptations resulting in pain relief without analgesic tolerance. © 2005 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005
Neuroscience Letters, 2006
Opiates are commonly used to treat moderate to severe pain and can be used over prolonged periods in states of chronic pain such as those associated with cancer. In addition, to analgesic actions, studies show that opiate administration can paradoxically induce hyperalgesia. At the pre-clinical level, such hyperalgesia is associated with numerous pronociceptive neuroplastic changes within the primary afferent fibers and the spinal cord. In rodents, sustained opiate administration also induces antinociceptive tolerance. The mechanisms by which prolonged opiate exposure induces hyperalgesia and the relationship of this state to antinociceptive tolerance remain unclear. The present study was aimed at determining whether sustained opiate-induced hyperalgesia, associated neuroplasticity and antinociceptive tolerance are the result of specific opiate interaction at opiate receptors. Enantiomers of oxymorphone, a mu opioid receptor agonist, were administered to rats by spinal infusion across 7 days. Sustained spinal administration of (−)-oxymorphone, but not its inactive enantiomer (+)-oxymorphone or vehicle, upregulated spinal dynorphin content, produced thermal and tactile hypersensitivity, and produced antinociceptive tolerance. These results indicate that these pronociceptive actions of sustained opiate administration require specific interaction with opiate receptors and are unlikely to be the result of accumulation of potentially excitatory metabolic products. While the precise mechanisms, which may account for these pronociceptive changes remain to be unraveled, the present data point to plasticity initiated by opiate receptor interaction.
Antinociceptive and nociceptive actions of opioids
Journal of Neurobiology, 2004
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). © 2004 Wiley Periodicals, Inc. J Neurobiol 61: 126–148, 2004
Opioids modulate pain facilitation from the dorsal reticular nucleus
Molecular and Cellular Neuroscience, 2008
During chronic pain, the supraspinal pain modulatory system undergoes plastic changes with enhancement of facilitation transmission at the spinal cord. The changes induced by chronic pain at descending modulation often affect opioidergic modulation, and were never described for a key facilitatory component of the system, the dorsal reticular nucleus (DRt). Neurochemical characterization of the DRt-spinal pathway showed that δ-opioid receptors are positioned as to indirectly modulate the activity of non-projecting DRt neurons, whereas neurons expressing μ-opioid receptors project to the spinal dorsal horn or act as interneurons, the latter of which co-expressing GABA B receptors. In monoarthritic rats, the expression of μopioid receptors decreased in the DRt whereas the levels of endogenous enkephalin remained unaltered. To increase the opioidergic inhibition of the DRt, we locally injected selective agonists of δand μ-opioid receptors or a viral vector containing the human preproenkephalin transgene. Injection of the Herpes Simplex viral vector encoding preproenkephalin induced thermal hypoalgesia in non-inflamed animals and hyperalgesia in monoarthritic rats. The opioid agonists [D-Ala 2 , Glu 4 ]-deltorphin (DELT) and [D-Ala 2 , NMePhe 4 Gly-ol 5 ]-enkephalin (DAMGO) induced thermal hyperalgesia in both non-inflamed and monoarthritic rats, but with lower doses in the latter group. The present study shows that opioidergic neurons at the DRt are modulated by GABAergic cells herein controlling the descending facilitation of pain transmission. The DRt exhibits plastic changes during chronic inflammatory pain, with decrease opioid receptor expression which may account for increased descending facilitation during chronic pain.
2001
Many clinical case reports have suggested that sustained opioid exposure can elicit unexpected, paradoxical pain. Here, we explore the possibility that (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and the presence of such pain manifests behaviorally as antinociceptive tolerance. Rats implanted subcutaneously with pellets or osmotic minipumps delivering morphine displayed time-related tactile allodynia and thermal hyperalgesia (i.e., opioid-induced "pain"); placebo pellets or saline minipumps did not change thresholds. Opioid-induced pain was observed while morphine delivery continued and while the rats were not in withdrawal. RVM lidocaine, or bilateral lesions of the dorsolateral funiculus (DLF), did not change response thresholds in placebo-pelleted rats but blocked opioid-induced pain. The intrathecal morphine antinociceptive dose-response curve (DRC) in morphinepelleted rats was displaced to the right of that in placebopelleted rats, indicating antinociceptive "tolerance." RVM lido-caine or bilateral DLF lesion did not alter the intrathecal morphine DRC in placebo-pelleted rats but blocked the rightward displacement seen in morphine-pelleted animals. The subcutaneous morphine antinociceptive DRC in morphinepelleted rats was displaced to the right of that in placebopelleted rats; this right shift was blocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pain decreases spinal opioid antinociceptive potency, and (3) blockade of pain restores antinociceptive potency, revealing no change in antinociceptive signal transduction. These studies offer a mechanism for paradoxical opioid-induced pain and allow the development of approaches by which the loss of analgesic activity of opioids might be inhibited.
Journal of Neuroscience, 2004
Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [ opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4 -L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAPpositive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.