Inhibition of spinal protein kinase C blocks substance P-mediated hyperalgesia

被引:39
作者
Wajima, Z [1 ]
Hua, XY [1 ]
Yaksh, TL [1 ]
机构
[1] Univ Calif San Diego, Dept Anesthesiol, La Jolla, CA 92093 USA
关键词
spinal cord; substance P; hyperalgesia;
D O I
10.1016/S0006-8993(00)02714-1
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Substance P (SP) is an important neuromediator in the spinal processing of nociceptive afferent information. Our previous study has shown that spinal (intrathecal, IT) application of SP produces thermal hyperalgesia that is mediated by activation of the G-protein coupled NK1 receptor. The activation of some classes of the G-protein coupled receptors is known to produce diacylglycerol with consequent activation of protein kinase C (PKC). In the present study, we have demonstrated that intrathecal administration of a selective PKC inhibitor GF109203X (GF, 0.73 nmol) in rats chronically implanted with intrathecal catheters 15 min prior to IT-SP (48 nmol) completely blocked the SP-induced thermal hyperalgesia. The effect of GF was dose-dependent (0.073-0.73 nmol), Bisindolymaleimide V, the inactive homolog of Gf, had no effect. Pretreatment with GF 3 h, but not 24 h, prior to SP still produced antinociception. Moreover, intrathecal treatment with GF (0.73 nmol) attenuated the formalin paw injection-induced flinching, preferentially at the 2nd phase, that is known to be associated with the release of endogenous SP at the spinal cord. These data suggest that activation of spinal PKC is involved in the SP-mediated hyperalgesia. Thus, SP. which is released in the spinal cord subsequent to persistent stimulation of small sensory afferents after tissue injury, may contribute to spinal hyperexcitability and persistent pain by enhancement of PKC-mediated phosphorylation of target molecules such as NMDA receptors. (C) 2000 Elsevier Science B.V. All rights reserved.
引用
收藏
页码:314 / 321
页数:8
相关论文
共 44 条
[1]  
CHAPLAN SR, 1994, J PHARMACOL EXP THER, V269, P1117
[2]  
Chaplan SR, 1997, J PHARMACOL EXP THER, V280, P829
[3]   THE EFFECT OF INTRATHECAL ADMINISTRATION OF RP67580, A POTENT NEUROKININ-1 ANTAGONIST ON NOCICEPTIVE TRANSMISSION IN THE RAT SPINAL-CORD [J].
CHAPMAN, V ;
DICKENSON, AH .
NEUROSCIENCE LETTERS, 1993, 157 (02) :149-152
[4]   PROTEIN-KINASE-C REDUCES MG2+ BLOCK OF NMDA-RECEPTOR CHANNELS AS A MECHANISM OF MODULATION [J].
CHEN, L ;
HUANG, LYM .
NATURE, 1992, 356 (6369) :521-523
[5]   SUSTAINED POTENTIATION OF NMDA RECEPTOR MEDIATED GLUTAMATE RESPONSES THROUGH ACTIVATION OF PROTEIN-KINASE-C BY A MU-OPIOID [J].
CHEN, L ;
HUANG, LYM .
NEURON, 1991, 7 (02) :319-326
[6]   A CURE FOR WIND UP - NMDA RECEPTOR ANTAGONISTS AS POTENTIAL ANALGESICS [J].
DICKENSON, AH .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1990, 11 (08) :307-309
[7]   Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli [J].
Dirig, DM ;
Salami, A ;
Rathbun, ML ;
Ozaki, GT ;
Yaksh, TL .
JOURNAL OF NEUROSCIENCE METHODS, 1997, 76 (02) :183-191
[8]   NEUROKININ-1 AND NEUROKININ-2 ANTAGONISTS ATTENUATE THE RESPONSES AND NK1-ANTAGONISTS PREVENT THE SENSITIZATION OF PRIMATE SPINOTHALAMIC TRACT NEURONS AFTER INTRADERMAL CAPSAICIN [J].
DOUGHERTY, PM ;
PALECEK, J ;
PALECKOVA, V ;
WILLIS, WD .
JOURNAL OF NEUROPHYSIOLOGY, 1994, 72 (04) :1464-1475
[9]   EXCITATORY AMINO ACID-MEDIATED COMPONENTS OF SYNAPTICALLY EVOKED INPUT FROM DORSAL ROOTS TO DEEP DORSAL HORN NEURONS IN THE RAT SPINAL-CORD SLICE [J].
GERBER, G ;
RANDIC, M .
NEUROSCIENCE LETTERS, 1989, 106 (1-2) :211-219
[10]   A NEW AND SENSITIVE METHOD FOR MEASURING THERMAL NOCICEPTION IN CUTANEOUS HYPERALGESIA [J].
HARGREAVES, K ;
DUBNER, R ;
BROWN, F ;
FLORES, C ;
JORIS, J .
PAIN, 1988, 32 (01) :77-88