Document Detail

Phospholipase Cbeta1 modulates pain sensitivity, opioid antinociception and opioid tolerance formation.
MedLine Citation:
PMID:  16405873     Owner:  NLM     Status:  MEDLINE    
Phospholipase C (PLC) activity has been implicated in multiple opioid-induced sequelae. The relevance of PLC-linked pathways to opioid actions is isoform-specific. Chronic morphine augments PLCbeta1 signaling while diminishing that of PLCbeta3. This suggests that PLCbeta1 makes an important contribution to opioid tolerance formation (PNAS 100: 13686-1369, 2003). In the present study, PLCbeta1 knockout animals (-/-) were used to assess the relevance of PLCbeta1 to pain thresholds, morphine antinociception and analgesic tolerance formation. Response latencies to thermal nociceptive stimuli were markedly diminished in -/- animals relative to their wild-type (+/+) and heterozygous (+/-) counterparts; thermal nociceptive thresholds obtained in +/+ and +/- mice did not differ. This suggests that the contribution of PLCbeta1 to thermal pain thresholds requires a critical concentration of PLCbeta1 protein. PLCbeta1 genotype also influenced acute and chronic responsiveness to morphine. Analgesic dose responsiveness and the magnitude of analgesic tolerance formation to morphine were significantly attenuated in -/- vs. +/+ animals. Notably, in contrast to thermal nociceptive thresholds, acute and chronic morphine responsiveness differed significantly only between +/+ and -/- genotypes and not between -/- vs. +/- groups. These data suggest that whereas the contribution of PLCbeta1 to thermal nociceptive response thresholds requires a critical concentration of PLCbeta1 protein, its participation in morphine analgesic and tolerance-producing mechanisms is graded. Importantly, GTPgammaS binding studies revealed that there is no detectable diminution in functional opioid receptors in spinal tissue from -/- animals. This underscores the importance of PLCbeta1 to morphine sequelae that are initiated downstream from the opioid receptor.
Nai-Jiang Liu; Hans vonGizycki; Alan R Gintzler
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural     Date:  2006-01-06
Journal Detail:
Title:  Brain research     Volume:  1069     ISSN:  0006-8993     ISO Abbreviation:  Brain Res.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2006-01-30     Completed Date:  2006-06-13     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  0045503     Medline TA:  Brain Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  47-53     Citation Subset:  IM    
Department of Biochemistry, State University of New York, Downstate Medical Center, Brooklyn, NY 11203, USA.
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MeSH Terms
Analysis of Variance
Blotting, Northern / methods
Blotting, Western / methods
Dose-Response Relationship, Drug
Drug Tolerance / physiology*
Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
Isoenzymes / deficiency,  physiology*
Mice, Knockout / physiology
Morphine / administration & dosage*,  adverse effects
Narcotics / administration & dosage*,  adverse effects
Pain Measurement / methods
Pain Threshold / drug effects,  physiology*
Phospholipase C beta
Protein Binding / drug effects
Reaction Time / genetics
Spinal Cord / cytology,  drug effects
Type C Phospholipases / deficiency,  physiology*
Grant Support
Reg. No./Substance:
0/Isoenzymes; 0/Narcotics; 37589-80-3/Guanosine 5'-O-(3-Thiotriphosphate); 57-27-2/Morphine; EC 3.1.4.-/Type C Phospholipases; EC C beta

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