Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 161, Issue 4, Pages 925-935Publisher
WILEY
DOI: 10.1111/j.1476-5381.2010.00935.x
Keywords
synaptic transmission; glycine; transporter; pain; dorsal horn; substantia gelatinosa; endocannabinoid; arachidonate
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Funding
- National Health & Medical Research Council of Australia [402564]
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BACKGROUND AND PURPOSE The arachidonyl-amino acid N-arachidonyl-glycine (NAGly) is an endogenous lipid, generated within the spinal cord and producing spinally mediated analgesia via non-cannabinoid mechanisms. In this study we examined the actions of NAGly on neurons within the superficial dorsal horn, a key site for the actions of many analgesic agents. EXPERIMENTAL APPROACH Whole cell patch clamp recordings were made from lamina II neurons in rat spinal cord slices to examine the effect of NAGly on glycinergic and NMDA-mediated synaptic transmission. KEY RESULTS N-arachidonyl-glycine prolonged the decay of glycine, but not beta-alanine induced inward currents and decreased the amplitude of currents induced by both glycine and beta-alanine. NAGly and ALX-1393 (inhibitor of the glycine transporter, GLYT2), but not the GLYT1 inhibitor, ALX-5407, produced a strychnine-sensitive inward current. ALX-5407 and ALX-1393, but not NAGly prolonged the decay phase of glycine receptor-mediated miniature inhibitory postsynaptic currents (IPSCs). NAGly prolonged the decay phase of evoked IPSCs, although to a lesser extent than ALX-5407 and ALX-1393. In the presence of ALX-1393, NAGly shortened the decay phase of evoked IPSCs. ALX-5407 increased and NAGly decreased the amplitude of evoked NMDA-mediated excitatory postsynaptic currents. CONCLUSIONS AND IMPLICATIONS Our results suggest that NAGly enhanced inhibitory glycinergic synaptic transmission within the superficial dorsal horn by blocking glycine uptake via GLYT2. In addition, NAGly decreased excitatory NMDA-mediated synaptic transmission. Together, these findings provide a cellular explanation for the spinal analgesic actions of NAGly.
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