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J Pharmacol Exp Ther. 1998 Feb;284(2):678-86.

Repetitive opioid abstinence causes progressive hyperalgesia sensitive to N-methyl-D-aspartate receptor blockade in the rat.

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  • 1Anesthesiology Research Laboratory, Department of Anesthesiology, Tufts University School of Medicine, Baystate Medical Center, Springfield, Massachusetts 01199, USA.


The opioid abstinence syndrome is associated with spinal excitatory amino acid (EAA) release, hyperalgesia and long-term changes in dorsal horn cellular excitability. N-Methyl-D-aspartate (NMDA) receptor antagonism attenuates opioid tolerance but also blocks EAA release during abstinence. This study examines the effect of repetitive abstinence, and NMDA receptor antagonism during abstinence, on thermal nociceptive thresholds and spinal tolerance. An intrathecal catheter system driven by a miniosmotic pump (Alzet 2002 0.5 microl/h) was implanted in rats (n = 4-8/group) and delivered alternating daily infusions of morphine (40 nmol/h), saline or MK801 (MK) (10 nmol/h). Abstinence was induced by infusion of saline or MK. Groups were: saline, 7 days; morphine, 7 days; abstinence (saline), day 6; abstinence (saline), days 4 and 6; abstinence (saline), days 2, 4 and 6; morphine, except on days 2, 4 and 6 when morphine (8 nmol/h) was infused; abstinence (MK), day 6; abstinence (MK), days 2, 4 and 6; and saline with MK, days 2, 4 and 6. Analgesia was measured daily (hot plate). Sixteen hours after termination of the infusion period (day 8) groups received intrathecal morphine (100 nmol) to assess tolerance. Hyperalgesia was most pronounced in groups subjected to repetitive abstinence, and least evident in groups in which continuous infusion was maintained or in which MK was administered during abstinence. MK administered during abstinence did not prevent tolerance. These results show that repetitive opioid abstinence is associated with progressive hyperalgesia mediated via NMDA receptor activation, but that NMDA receptor antagonism during such periods of abstinence does not prevent progressive opioid tolerance.

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