Functional evidence for interaction between prostaglandin EP3 and kappa-opioid receptor pathways in tactile pain induced by human immunodeficiency virus type-1 (HIV-1) glycoprotein gp120.
HIV-1 glycoprotein gp120 administered intrathecally induces tactile pain (allodynia) in animals. In the present study, we investigated the mechanism of gp120-induced allodynia and possible functional connections with factors modulating pain transmission at the spinal level. Gp120 evoked allodynia in a dose-dependent manner with the maximum effect at 1 pg/mouse, and stimulated a rapid increase in intracellular free Ca2+ concentration ([Ca2+]i) in the dorsal horn cells of the spinal cord. These responses evoked by gp120 were blocked by galactocerebroside. The gp120-induced allodynia was also attenuated by the non-steroidal anti-inflammatory drug indomethacin, which inhibits prostaglandin synthesis, and did not develop in mice lacking the EP3 prostaglandin E receptor subtype (EP3(-/-)). Pretreatment of spinal slices with indomethacin dose-dependently decreased the percentage of the cells that showed increased [Ca2+]i in response to gp120, and the decrease was reversed by addition of the selective EP3 agonist ONO-AE-248. The kappa-opioid agonist U-50,488 significantly enhanced the gp120-stimulated increase in [Ca2+]i in spinal slices prepared from EP3(-/-) mice, and the simultaneous addition of U-50,488 with gp120 reproduced the gp120-induced allodynia in EP3(-/-) mice. These results suggest that gp120 induced allodynia by increasing [Ca2+]i, concomitant with activation of prostanoid EP3 and kappa-opioid receptors in the spinal cord.
Minami
Toshiaki
T
Department of Anesthesiology, Osaka Medical College, Takatsuki 569-8686, Japan.
Matsumura
Shinji
S
Mabuchi
Tamaki
T
Kobayashi
Takuya
T
Sugimoto
Yukihiko
Y
Ushikubi
Fumitaka
F
Ichikawa
Atsushi
A
Narumiya
Shuh
S
Ito
Seiji
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism* / Q000633:toxicity; D015497:HIV-1; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D010147:Pain Measurement; D010812:Physical Stimulation; D011453:Prostaglandins / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000235:genetics; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D014110:Touch
D015699:HIV Envelope Protein gp120; C545644:PTGER2 protein, human; C545647:PTGER3 protein, human; D011453:Prostaglandins; C545645:Ptger2 protein, mouse; C545648:Ptger3 protein, mouse; D017473:Receptors, Opioid, kappa; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D002118:Calcium