Hyperalgesia In Wild-type Mice Research Articles

Thalamic Control of Visceral Nociception Mediated by T-Type Ca 2+ Channels

Sensations from viscera, like fullness, easily become painful if the stimulus persists. Mice lacking alpha1G T-type Ca2+ channels show hyperalgesia to visceral pain. Thalamic infusion of a T-type blocker induced similar hyperalgesia in wild-type mice. In response to visceral pain, the ventroposterolateral thalamic neurons evokeda surge of single spikes, which then slowly decayed as T type-dependent burst spikes gradually increased. In alpha1G-deficient neurons, the single-spike response persisted without burst spikes. These results indicate that T-type Ca2+ channels underlie an antinociceptive mechanism operating in the thalamus andsupport the idea that burst firing plays a critical role in sensory gating in the thalamus.

The use of kinin B 1 and B 2 receptor knockout mice and selective antagonists to characterize the nociceptive responses caused by kinins at the spinal level

The mechanisms by which kinins induce hyperalgesia in the spinal cord were investigated by using B 1 or B 2 knockout mice in conjunction with kinin selective agonists and antagonists. The i.t. administration of the kinin B 2 receptor agonists, bradykinin (BK) or Tyr 8-BK produced dose-related thermal hyperalgesia evaluated in the hot-plate test. BK-induced hyperalgesia was abolished by the B 2 receptor antagonist Hoe 140. The i.t. injection of the kinin B 1 receptor agonists, des-Arg 9-bradykinin (DABK) or des-Arg 10-kallidin (DAKD) also caused dose-related thermal hyperalgesia. Different from the B 2 agonists, the i.t. injection of DABK or DAKD caused a weak, but prolonged hyperalgesia, an effect that was blocked by the B 1 receptor antagonist des-Arg 9-[Leu 8]-bradykinin (DALBK). The i.t. injection of BK caused thermal hyperalgesia in wild-type mice (WT) and in the B 1 receptor knockout mice (B 1R KO), but not in the B 2 receptor knockout mice (B 2R KO). Similarly, the i.t. injection of DABK elicited thermal hyperalgesia in WT mice, but not in B 1R KO mice. However, DABK-induced hyperalgesia was more pronounced in the B 2R KO mice when compared with the WT mice. The i.t. injection of Hoe 140 or DALBK inhibited the second phase of formalin (F)-induced nociception. Furthermore, i.t. Hoe 140, but not DALBK, also inhibits the first phase of F response. Finally, the i.t. injection of DALBK, but not of Hoe 140, inhibits the long-term thermal hyperalgesia observed in the ipsilateral and in contralateral paws after intraplantar injection with complete Freund’s adjuvant. These findings provide evidence that kinins acting at both B 1 and B 2 receptors at the spinal level exert a critical role in controlling the nociceptive processing mechanisms. Therefore, selective kinin antagonists against both receptors are of potential interest drugs to treat some pain states.

Absence of prostaglandin E2-induced hyperalgesia in NMDA receptor epsilon subunit knockout mice.

1. We have previously found that intrathecal administration of prostaglandins E2 (PGE2) and D2 (PGD2) into conscious mice induced hyperalgesia by the hot plate test. The present study investigated the involvement of N-methyl-D-aspartate (NMDA) receptor in the prostaglandin-induced hyperalgesia by use of mice tacking NMDA receptor epsilon 1, epsilon 4, or epsilon 1/epsilon 4 subunits. 2. PGE2 induced hyperalgesia over a wide range of doses from 50 pg to 500 ng kg-1 in wild-type mice. But PGE2 could not induce hyperalgesia in epsilon 1, epsilon 4, or epsilon 1/epsilon 4 subunit knockout mice. 3. The NMDA receptor antagonist D-(-)-2-amino-5-phosphonovaleric acid (D-AP5), the non-NMDA receptor antagonist 7-D-glutamylaminomethyl sulphonic acid (GAMS), and the nitric oxide synthase inhibitor N epsilon-nitro-L-arginine methyl ester (L-NAME) inhibited the PGE2-induced hyperalgesia in wild-type mice. 4. PGD2 induced hyperalgesia at doses of 25 ng to 250 ng kg-1 in both wild-type and epsilon 1/epsilon 4 subunit knockout mice. The substance P receptor antagonist OP 96.345 blocked the PGD2-induced hyperalgesia in wild-type and epsilon 1/epsilon 4 subunit knockout mice. 5. These results demonstrate that the pathways leading to hyperalgesia are different between PGD2 and PGE2, and that both epsilon 1 and epsilon 4 subunits of the NMDA receptor are involved in the PGE2-induced hyperalgesia.