Morphine-3beta-D-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa.

Abstract

High doses of intrathecally applied morphine or morphine-3beta-D-glucuronide (M3G) produce allodynia and hyperalgesia. Whole-cell patch-clamp recordings were made from substantia gelatinosa neurons in transverse slices of adult rat lumbar spinal cord to compare the actions of M3G with those of the mu-opioid agonist, DAMGO ([D-Ala(2),N-Met-Phe(4),Gly-ol(5)]-enkephalin), and the ORL(1) agonist, nociceptin/orphanin FQ (N/OFQ). M3G (1-100 microM) had little or no effect on evoked excitatory postsynaptic currents (EPSC) and no effect on postsynaptic membrane conductance. In contrast, 1 microM DAMGO and 1 microM N/OFQ reduced the amplitude of evoked EPSCs and activated an inwardly rectifying K(+) conductance. M3G did not attenuate the effect of DAMGO or N/OFQ on evoked EPSC amplitude. However, 1 to 100 microM M3G reduced the amplitude of evoked GABAergic and glycinergic inhibitory postsynaptic current (IPSC) by up to 48%. This effect was naloxone-insensitive. The evoked IPSC was also attenuated by DAMGO, but not by N/OFQ. Because M3G reduced the frequency of tetrodotoxin-insensitive miniature IPSCs and increased paired-pulse facilitation, it appeared to act presynaptically to disinhibit substantia gelatinosa neurons. This effect, which does not appear to involve mu-opioid or ORL(1) receptors, may contribute to the allodynia and hyperalgesia observed after intrathecal application of high doses of morphine.

• Authors: Timothy D Moran, Peter A Smith
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 302 Issue 2 Pg. 568-76 (Aug 2002) ISSN: 0022-3565 [Print] United States
• PMID: 12130717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Central Nervous System Stimulants
• Morphine Derivatives
• Opioid Peptides
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
• nociceptin
• Strychnine
• morphine-3-glucuronide

Topics

• Animals
• Central Nervous System Stimulants (pharmacology)
• Electric Stimulation
• Enkephalin, Ala(2)-MePhe(4)-Gly(5)- (pharmacology)
• Excitatory Postsynaptic Potentials (drug effects, physiology)
• Morphine Derivatives (pharmacology)
• Opioid Peptides (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Strychnine (pharmacology)
• Substantia Gelatinosa (drug effects, physiology)
• Synaptic Transmission (drug effects)