Novel Antiangiogenic Effects of the Bisphosphonate Compound Zoledronic Acid

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Abstract
High doses of intrathecally applied morphine or morphine-3β-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 μ-opioid agonist, DAMGO ([d-Ala2,N-Met-Phe4,Gly-ol5]-enkephalin), and the ORL1 agonist, nociceptin/orphanin FQ (N/OFQ). M3G (1–100 μM) had little or no effect on evoked excitatory postsynaptic currents (EPSC) and no effect on postsynaptic membrane conductance. In contrast, 1 μM DAMGO and 1 μM 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 μM 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 μ-opioid or ORL1 receptors, may contribute to the allodynia and hyperalgesia observed after intrathecal application of high doses of morphine.