Modulatory effect of CCK-8S on GABA-induced depolarization from rat dorsal root ganglion.
CCK is a brain-gut peptide that is abundantly distributed in both gastrointestinal tract and mammalian brain. The sulfated octapeptide fragment of cholecystokinin (CCK-8S) has been shown to be involved in numerous physiological functions such as behavior, anxiety, learning/memory processes and neuropathic pain. CCK-8S is one of the strongest endogenous anti-opioid substances and suppresses opioid peptides-mediated 'pre-synaptic inhibition' of gamma-aminobutyric acid (GABA) release. Here we provide evidence that CCK-8S modulates GABA-evoked membrane depolarization in rat dorsal root ganglion (DRG) neurons using intracellular recording technique. Bath application CCK-8S-induced membrane depolarization in most of the rat DRG neurons. The depolarization was blocked by prolumide but not LY225910. Pretreatment with CCK-8S suppressed the GABA-evoked depolarization in a concentration-dependent manner. The CCK-8S inhibition was also time-dependent and reached the peak at about 2 min. The inhibitory effect of CCK-8S was strongly suppressed by pre-incubation of CCK-B receptor antagonist LY225910, phospholipase C inhibitor U73122, protein kinase C inhibitor chelerythrine and calcium chelator BAPTA-AM, respectively. The protein kinase A inhibitor H-89 did not affect CCK-8S effect. The results suggest that CCK-8S inhibits GABA-A receptor function by activation of CCK-B receptor followed by activation of intracellular PLC-Ca(2+)-PKC cascade. Thus, CCK-8S might enhance nociceptive information transmission through inhibition of the "pre-synaptic inhibition" evoked by GABA, which may explain its role in modulation of primary sensory information (especially pain).
Ma
Ke-Tao
KT
The Fundamental Medical School of Wuhan University, Hubei 430071, P.R. China.
Si
Jun-Qiang
JQ
Zhang
Zhi-Qin
ZQ
Zhao
Lei
L
Fan
Ping
P
Jin
Jin-Lan
JL
Li
Xin-Zhi
XZ
Zhu
Li
L
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D012844:Sincalide / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D005680:gamma-Aminobutyric Acid; D012844:Sincalide