Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons

Leon W Fyfe; Daniel R Cleary; Tara A Macey; Michael M Morgan; Susan L Ingram

doi:10.1124/jpet.110.172643

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Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons

Journal article

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Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons

Leon W Fyfe, Daniel R Cleary, Tara A Macey, Michael M Morgan and Susan L Ingram

The Journal of pharmacology and experimental therapeutics, Vol.335(3), pp.674-680

12/2010

DOI: https://doi.org/10.1124/jpet.110.172643

Handle:

https://hdl.handle.net/2376/110940

PMCID: PMC2993552

PMID: 20739455

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Abstract

Naltrexone - analogs & derivatives

Analgesics - pharmacology

Periaqueductal Gray - drug effects

Drug Tolerance - physiology

Male

Receptors, Opioid, mu - agonists

Enkephalin, Methionine - pharmacology

Naltrexone - pharmacology

Reaction Time - drug effects

Neurons - physiology

Neurons - drug effects

Morphine - pharmacology

Enkephalin, Ala-MePhe-Gly- - pharmacology

Electrophysiological Phenomena - physiology

Analgesics - administration & dosage

Inhibitory Postsynaptic Potentials - physiology

Rats

Receptors, Opioid, mu - antagonists & inhibitors

Rats, Sprague-Dawley

Patch-Clamp Techniques

Animals

Signal Transduction - drug effects

Periaqueductal Gray - physiology

Pain Measurement

Morphine - administration & dosage

Inhibitory Postsynaptic Potentials - drug effects

Electrophysiological Phenomena - drug effects

Opioids activate the descending antinociceptive pathway from the ventrolateral periaqueductal gray (vlPAG) by both pre- and postsynaptic inhibition of tonically active GABAergic neurons (i.e., disinhibition). Previous research has shown that short-term desensitization of postsynaptic μ-opioid receptors (MOPrs) in the vlPAG is increased with the development of opioid tolerance. Given that pre- and postsynaptic MOPrs are coupled to different signaling mechanisms, the present study tested the hypothesis that short-term desensitization of presynaptic MOPrs also contributes to opioid tolerance. Twice-daily injections of morphine (5 mg/kg s.c.) for 2 days caused a rightward shift in the morphine dose-response curve on the hot plate test (D(50) = 9.9 mg/kg) compared with saline-pretreated (5.3 mg/kg) male Sprague-Dawley rats. In vitro whole-cell patch-clamp recordings from vlPAG slices revealed that inhibition of evoked inhibitory postsynaptic currents (eIPSCs) by the MOPr-selective agonist [d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin was decreased in morphine-tolerant (EC(50) = 708 nM) compared with saline-pretreated rats (EC(50) = 163 nM). However, short-term desensitization of MOPr inhibition of eIPSCs was not observed in either saline- or morphine-pretreated rats. Reducing the number of available MOPrs with the irreversible opioid receptor antagonist, β-chlornaltrexamine decreased maximal MOPr inhibition with no evidence of desensitization, indicating that the lack of observed desensitization is not caused by receptor reserve. These results demonstrate that tolerance to the antinociceptive effect of morphine is associated with a decrease in presynaptic MOPr sensitivity or coupling to effectors, but this change is independent of short-term MOPr desensitization.

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Title: Tolerance to the antinociceptive effect of morphine in the absence of short-term presynaptic desensitization in rat periaqueductal gray neurons
Creators: Leon W Fyfe - Department of Psychology, Washington State University, Vancouver, Washington 98686, USA
Daniel R Cleary
Tara A Macey
Michael M Morgan
Susan L Ingram
Publication Details: The Journal of pharmacology and experimental therapeutics, Vol.335(3), pp.674-680
Academic Unit: Psychology, Department of
Publisher: United States
Grant note: R01 DA024041-05 / NIDA NIH HHS R01 DA024041 / NIDA NIH HHS R01 DA015498 / NIDA NIH HHS DA015498 / NIDA NIH HHS
Identifiers: 99900547273601842
Language: English
Resource Type: Journal article