Morphine-3-D-glucuronide Suppresses Inhibitory Synaptic Transmission in Rat Substantia Gelatinosa

High doses of intrathecally applied morphine or morphine-3-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 -opioid agonist, DAMGO ([D-Ala2,N-Met-Phe4,Gly-ol5]-en-kephalin), and the ORL1 agonist, nociceptin/orphanin FQ (N/ OFQ). M3G (1–100 M) had little or no effect on evoked exci-tatory postsynaptic currents (EPSC) and no effect on postsynaptic membrane conductance. In contrast, 1 M DAMGO and 1 M 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 M 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 fre-quency of tetrodotoxin-insensitive miniature IPSCs and in-creased paired-pulse facilitation, it appeared to act presynap-tically to disinhibit substantia gelatinosa neurons. This effect, which does not appear to involve -opioid or ORL1 receptors, may contribute to the allodynia and hyperalgesia observed after intrathecal application of high doses of morphine. Morphine is widely used for the management of moder-ate to severe pain. It is converted by glucuronidation into two major metabolites, morphine-3-D-glucuronide (M3G) and morphine-6-D-glucuronide (M6G) (Boerner et al., 1975; Christrup, 1997). M6G has high affinity for the -opioid receptor (Pasternak et al., 1987; Paul et al., 1989; Löser et al., 1996) and appears to be a more potent opioid agonist than morphine (Pasternak et al., 1987; Paul et al.