PMID- 12736633
OWN - NLM
STAT- MEDLINE
DCOM- 20030611
LR  - 20150311
IS  - 0893-133X (Print)
IS  - 0893-133X (Linking)
VI  - 28
IP  - 5
DP  - 2003 May
TI  - The phospholipase C-IP3 pathway is involved in muscarinic antinociception.
PG  - 888-97
AB  - The cellular events involved in muscarinic analgesia were investigated in the 
      mouse hot-plate test. Intracerebroventricular (i.c.v.) pretreatment with 
      antisense oligonucleotides (aODNs) against the alpha subunit of G(q) and G(11) 
      proteins prevented the analgesia induced by physostigmine and oxotremorine. 
      Furthermore, administration of the phospholipase C (PLC) inhibitor U-73122, as 
      well as the injection of an aODN complementary to the sequence of PLCbeta(1), 
      antagonized the increase of the pain threshold induced by both cholinomimetic 
      drugs. In mice undergoing treatment with LiCl, which impairs phosphatidylinositol 
      synthesis, or treatment with heparin, an IP(3) receptor antagonist, the 
      antinociception induced by physostigmine and oxotremorine was dose-dependently 
      antagonized. I.c.v. pretreatment with TMB-8, a blocker of Ca(2+) release from 
      intracellular stores, prevented the increase of pain threshold induced by the 
      investigated cholinomimetic drugs. Coadministration of Ca(2+) restored the 
      muscarinic analgesia in LiCl, heparin, and TMB-8-preatreated mice. On the other 
      hand, i.c.v. pretreatment with the selective protein kinase C (PKC) inhibitor 
      calphostin C, resulted in a dose-dependent enhancement of physostigmine- and 
      oxotremorine-induced antinociception. The administration of PKC activators, such 
      as PMA and PDBu, dose dependently prevented the cholinomimetic drug-induced 
      increase of pain threshold. Neither aODNs nor pharmacological treatments employed 
      produced any behavioral impairment of mice as revealed by the rota-rod and 
      hole-board tests. These results indicate a role for the PLC-IP(3) pathway in 
      central muscarinic analgesia in mice. Furthermore, activation of PKC by 
      cholinomimetic drugs may represent a pathway of negative modulation of muscarinic 
      antinociception.
FAU - Galeotti, Nicoletta
AU  - Galeotti N
AD  - Department of Preclinical and Clinical Pharmacology, University of Florence, 
      Viale G. Pieraccini 6, I-10539 Florence, Italy.
FAU - Bartolini, Alessandro
AU  - Bartolini A
FAU - Ghelardini, Carla
AU  - Ghelardini C
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20021111
PL  - England
TA  - Neuropsychopharmacology
JT  - Neuropsychopharmacology : official publication of the American College of 
      Neuropsychopharmacology
JID - 8904907
RN  - 0 (Analgesics)
RN  - 0 (Cholinesterase Inhibitors)
RN  - 0 (Estrenes)
RN  - 0 (Pyrrolidinones)
RN  - 0 (Receptors, Muscarinic)
RN  - 112648-68-7 
      (1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione)
RN  - 85166-31-0 (Inositol 1,4,5-Trisphosphate)
RN  - 9U1VM840SP (Physostigmine)
RN  - EC 3.1.4.- (Type C Phospholipases)
SB  - IM
MH  - Analgesics/*pharmacology
MH  - Animals
MH  - Cholinesterase Inhibitors/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Estrenes/pharmacology
MH  - Inositol 1,4,5-Trisphosphate/*physiology
MH  - Male
MH  - Mice
MH  - Pain Measurement/*drug effects/methods
MH  - Physostigmine/pharmacology
MH  - Pyrrolidinones/pharmacology
MH  - Receptors, Muscarinic/*metabolism
MH  - *Signal Transduction/drug effects/physiology
MH  - Type C Phospholipases/antagonists & inhibitors/metabolism/*physiology
EDAT- 2003/05/09 05:00
MHDA- 2003/06/12 05:00
CRDT- 2003/05/09 05:00
PHST- 2003/05/09 05:00 [pubmed]
PHST- 2003/06/12 05:00 [medline]
PHST- 2003/05/09 05:00 [entrez]
AID - 1300111 [pii]
AID - 10.1038/sj.npp.1300111 [doi]
PST - ppublish
SO  - Neuropsychopharmacology. 2003 May;28(5):888-97. doi: 10.1038/sj.npp.1300111. Epub 
      2002 Nov 11.