Morphine-3beta-D-glucuronide suppresses inhibitory synaptic transmission in rat substantia gelatinosa.
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.
Moran
Timothy D
TD
Department of Pharmacology, University Centre for Neuroscience, University of Alberta, Edmonton, Alberta, Canada T6G 2H7.
Smith
Peter A
PA
D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009022:Morphine Derivatives / Q000494:pharmacology*; D018847:Opioid Peptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013331:Strychnine / Q000494:pharmacology; D013376:Substantia Gelatinosa / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects*; D000097629:Nociceptin
D000697:Central Nervous System Stimulants; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D009022:Morphine Derivatives; D018847:Opioid Peptides; D013331:Strychnine; D000097629:Nociceptin; C018108:morphine-3-glucuronide