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Journal of Neuroscience, Vol 14, 2301-2312, Copyright © 1994 by Society for Neuroscience
Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C
J Mao, DD Price and DJ Mayer
Department of Anesthesiology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
In a rat model of morphine tolerance, we examined the hypotheses that
thermal hyperalgesia to radiant heat develops in association with the
development of morphine tolerance and that both the development and
expression of thermal hyperalgesia in morphine-tolerant rats are mediated
by central NMDA and non-NMDA receptors and subsequent protein kinase C
(PKC) activation. Tolerance to the analgesic effect of morphine was
developed in rats utilizing an intrathecal repeated treatment regimen. The
development of morphine tolerance and thermal hyperalgesia was examined by
employing the tail-flick test and paw- withdrawal test, respectively.
Intrathecal MK 801 (an NMDA receptor antagonist),
6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; a non-NMDA receptor
antagonist), or GM1 ganglioside (an intracellular PKC inhibitor) treatment
was given to examine the effects of these agents on the development and
expression of thermal hyperalgesia in morphine- tolerant rats. Tolerance to
the analgesic effect of morphine was reliably developed in rats following
once daily intrathecal (onto the lumbosacral spinal cord) injection of 10
micrograms of morphine sulfate for 8 consecutive days as demonstrated by
the decreased analgesia following morphine administration on day 8 as
compared to that on day 1. In association with the development of morphine
tolerance, thermal hyperalgesia to radiant heat developed in these same
rats. Paw- withdrawal latencies were reliably decreased in
morphine-tolerant rats as compared to nontolerant (saline) controls when
tested on day 8 before the last morphine treatment and on day 10 (i.e., 48
hr after the last morphine treatment). The coincident development of
morphine tolerance and thermal hyperalgesia was potently prevented by
intrathecal coadministration of morphine with MK 801 (10 nmol) or GM1 (160
nmol), and partially by CNQX (80 nmol). MK 801 (5, 10 nmol, not 2.5 nmol)
and CNQX (80, 160 nmol, not 40 nmol), but not GM1 (160 nmol), also reliably
reversed thermal hyperalgesia in rats rendered tolerant to morphine when
tested 30 min after each drug treatment on day 10 (48 hr after the last
morphine treatment). The data indicate that thermal hyperalgesia develops
in association with the development of morphine tolerance and that the
coactivation of central NMDA and non-NMDA receptors is crucial for both the
development and expression of thermal hyperalgesia in morphine-tolerant
rats. Furthermore, intracellular PKC activation plays a critical role in
the development of thermal hyperalgesia in morphine-tolerant rats.(ABSTRACT
TRUNCATED AT 400 WORDS)
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