Biphasic effects of chronic intrathecal gabapentin administration on the expression of protein kinase C gamma in the spinal cord of neuropathic pain rats.
OBJECTIVE
Patients suffering from neuropathic pain are difficult to treat and many methods are used to resolve this issue. In this study, we used a model of neuropathic pain comprising rats with chronic constriction injury (CCI) on the left sciatic nerve to investigate the chronic effect of gabapentin via intrathecal administration. We also observed the expression of dorsal spinal protein kinase C gamma subunit (PKCγ) and other pain-related molecules in the spinal area which included cyclooxygenase 2 (COX2), c-Fos and cyclic AMP-dependent transcription factor (ATF3) in the neuropathic pain animals.


METHODS
Male Sprague-Dawley (SD) rats (250-380 g) were randomly assigned to four groups, i.e., control, gabapentin (Gaba), MK801, and gabapentin plus MK801 (Gaba+M) groups. A PE-5 catheter was inserted into the lumbar spine area via the cervical spine area. CCI was performed the following day after the intrathecal catheter implant surgery. Gabapentin (1.05 μmol/day) was then given the following day after CCI surgery. Intrathecal gabapentin was administrated for 14 consecutive days. Pain-related behavior was assessed every 2 days thereafter by measuring the latency of foot withdrawal elicited by noxious radiant heat or Von Frey microfilament applied to the hind-paw plantar surface. MK801 (30 μg/day), an N-methyl-D-aspartate (NMDA) receptor blocker, was also added for potential effect. The tissue of dorsal horn of the lumbar spine was harvested on the 14(th) day for the expression of COX2, c-Fos, ATF3 and PKCγ with Western blotting, and positive finding protein was then checked on 7(th) day for further evaluation.


RESULTS
The beneficial effect of intrathecal gabapentin of statistic significance on thermal duration and mechanical microfilament appeared after 7-day and 11-day consecutive treatment, respectively. Furthermore, the NMDA receptor blocker also potentiated the effect on the behavior of thermal and mechanical stimulations. Gabapentin had no effect on the expression of COX2, c-Fos and ATF3. Interestingly, the expression of PKCγ in the spinal cord was initially inhibited by gabapentin on the 7(th) day but was potentiated on the 14(th) day.


CONCLUSIONS
Our results indicate that chronic intrathecal gabapentin has beneficial effects on the behaviors of both thermal and mechanical stimulations in the neuropathic pain animals and the NMDA blocker can potentiate this effect. Furthermore, gabapentin has biphasic effect on the expression of PKCγ in the spinal cord on Day 7 and Day 14 for the model rats with CCI.
Department of Anesthesiology, Tainan Hospital, Tainan City, Taiwan, ROC.
Chin-Yi
CY
Yeh
Shih-Chieh
SC
Chung
Fan-Ling
FL
Tseng
Yu-Chuan
YC
Tsai
Yen-Chin
YC
Liu
D000588:Amines / Q000008:administration & dosage / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D000077206:Gabapentin; D007278:Injections, Spinal; D008297:Male; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D011493:Protein Kinase C / Q000032:analysis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000494:pharmacology*
D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin; D016291:Dizocilpine Maleate; C087857:protein kinase C gamma; D011493:Protein Kinase C