Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance

Many clinical case reports have suggested that sustained opioid exposure ca n elicit unexpected, paradoxical pain. Here, we explore the possibility tha t (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and (2) 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 bil ateral lesions of the dorsolateral funiculus (DLF), did not change response thresholds in placebo-pelleted rats but blocked opioid-induced pain. The i ntrathecal morphine antinociceptive dose-response curve (DRC) in morphine-p elleted rats was displaced to the right of that in placebo-pelleted rats, i ndicating antinociceptive "tolerance." RVM lidocaine or bilateral DLF lesio n did not alter the intrathecal morphine DRC in placebo-pelleted rats but b locked the rightward displacement seen in morphine-pelleted animals. The su bcutaneous morphine antinociceptive DRC in morphine-pelleted rats was displ aced to the right of that in placebo-pelleted rats; this right shift was bl ocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pa in decreases spinal opioid antinociceptive potency, and (3) blockade of pai n 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.