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

被引:242
作者
Vanderah, TW
Suenaga, NMH
Ossipov, MH
Malan, TP
Lai, J
Porreca, F
机构
[1] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA
[2] Univ Arizona, Dept Anesthesiol, Tucson, AZ 85724 USA
关键词
descending facilitation; opioid-induced pain; opioid tolerance; supraspinal/spinal synergy; lidocaine; tactile allodynia; thermal hyperalgesia;
D O I
10.1523/JNEUROSCI.21-01-00279.2001
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 (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 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 morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats, indicating antinociceptive "tolerance." RVM lidocaine 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 morphine-pelleted rats was displaced to the right of that in placebo-pelleted 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.
引用
收藏
页码:279 / 286
页数:8
相关论文
共 51 条
  • [2] CLINICAL-EXPERIENCE OF LONG-TERM TREATMENT WITH EPIDURAL AND INTRATHECAL OPIOIDS - A NATIONWIDE SURVEY
    ARNER, S
    RAWAL, N
    GUSTAFSSON, LL
    [J]. ACTA ANAESTHESIOLOGICA SCANDINAVICA, 1988, 32 (03) : 253 - 259
  • [3] HYPERALGESIA DURING NALOXONE-PRECIPITATED WITHDRAWAL FROM MORPHINE IS ASSOCIATED WITH INCREASED ON-CELL ACTIVITY IN THE ROSTRAL VENTROMEDIAL MEDULLA
    BEDERSON, JB
    FIELDS, HL
    BARBARO, NM
    [J]. SOMATOSENSORY AND MOTOR RESEARCH, 1990, 7 (02) : 185 - 203
  • [4] Loss of antiallodynic and antinociceptive spinal supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum
    Bian, D
    Ossipov, MH
    Ibrahim, M
    Raffa, RB
    Tallarida, RJ
    Malan, TP
    Lai, J
    Porreca, F
    [J]. BRAIN RESEARCH, 1999, 831 (1-2) : 55 - 63
  • [5] SPINAL PROJECTIONS FROM MIDBRAIN IN MONKEY
    CASTIGLIONI, AJ
    GALLAWAY, MC
    COULTER, JD
    [J]. JOURNAL OF COMPARATIVE NEUROLOGY, 1978, 178 (02) : 329 - 345
  • [6] Long-lasting hyperalgesia induced by fentanyl in rats -: Preventive effect of ketamine
    Célèrier, E
    Rivat, C
    Jun, Y
    Laulin, JP
    Larcher, A
    Reynier, P
    Simonnet, G
    [J]. ANESTHESIOLOGY, 2000, 92 (02) : 465 - 472
  • [7] Evidence for opiate-activated NMDA processes masking opiate analgesia in rats
    Célèrier, E
    Laulin, JP
    Larcher, A
    Le Moal, M
    Simonnet, G
    [J]. BRAIN RESEARCH, 1999, 847 (01) : 18 - 25
  • [8] QUANTITATIVE ASSESSMENT OF TACTILE ALLODYNIA IN THE RAT PAW
    CHAPLAN, SR
    BACH, FW
    POGREL, JW
    CHUNG, JM
    YAKSH, TL
    [J]. JOURNAL OF NEUROSCIENCE METHODS, 1994, 53 (01) : 55 - 63
  • [9] CHERNY NI, 1999, TXB PAIN, P1479
  • [10] Colpaert FC, 1996, PHARMACOL REV, V48, P355