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

Neuropharmacology. 2003 Jul;45(1):96-105. doi: 10.1016/s0028-3908(03)00133-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • HIV Envelope Protein gp120 / metabolism*
  • HIV Envelope Protein gp120 / toxicity
  • HIV-1*
  • In Vitro Techniques
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Pain / chemically induced
  • Pain / metabolism*
  • Pain / physiopathology
  • Pain Measurement
  • Physical Stimulation
  • Prostaglandins / physiology*
  • Receptors, Opioid, kappa / agonists
  • Receptors, Opioid, kappa / physiology*
  • Receptors, Prostaglandin E / genetics
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP3 Subtype
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology
  • Touch


  • HIV Envelope Protein gp120
  • PTGER2 protein, human
  • PTGER3 protein, human
  • Prostaglandins
  • Ptger2 protein, mouse
  • Ptger3 protein, mouse
  • Receptors, Opioid, kappa
  • Receptors, Prostaglandin E
  • Receptors, Prostaglandin E, EP2 Subtype
  • Receptors, Prostaglandin E, EP3 Subtype
  • Calcium