[D-Pen2-D-Pen5]enkephalin, a delta opioid agonist, given intracerebroventricularly in the mouse produces antinociception through medication of spinal GABA receptors.
Intracerebroventricular (ICV) administration of [D-Pen2-D-Pen5]enkephalin (DPDPE), a delta opioid receptor agonist, activates a descending antinociceptive pathway that inhibits the tail-flick response in mice. Involvement of spinal GABA receptors in this response was studied by giving GABA antagonist intrathecally. First, antinociception produced by intrathecally administered isoguvacine, a GABAA agonist, was inhibited by intrathecal bicuculline (GABA receptor antagonist) or picrotoxin (chloride channel antagonist). Then, antinociception induced by ICV DPDPE was antagonized by intrathecal picrotoxin and bicuculline in a dose-and time-dependent manner. Second, intrathecal administration of 2-hydroxysaclofen, a GABAB antagonist (which inhibited antinociception induced by a GABAB agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABAA agonist, baclofen, given IT), produced a shift of the dose-response curve for ICV DPDPE to the right. GABAA and B antagonists given together intrathecally produced a greater than additive antagonistic effect against ICV DPDPE-induced antinociception. Thus, the delta agonist action of DPDPE in the brain leads to activation of descending spinal pathways which involve mediation by spinal GABAA and GABAB receptors in the antinociceptive response.
Holmes
B B
BB
Research Service, VA Medical Center, Milwaukee, WI.
Fujimoto
J M
JM
D000700:Analgesics / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D007539:Isonicotinic Acids / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010147:Pain Measurement / Q000187:drug effects; D018079:Receptors, GABA / Q000187:drug effects*; D017465:Receptors, Opioid, delta / Q000819:agonists*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D000700:Analgesics; D004745:Enkephalins; D018755:GABA Agonists; D058787:GABA-A Receptor Antagonists; D058788:GABA-B Receptor Antagonists; D007539:Isonicotinic Acids; D018079:Receptors, GABA; D017465:Receptors, Opioid, delta; D020881:Enkephalin, D-Penicillamine (2,5)-; C015300:isoguvacine