Antisense knockdown of spinal-mGluR1 reduces the sustained phase of formalin-induced nociceptive responses.

To examine the role of mGluR1 (a subunit of the group I metabotropic glutamate receptor) in the nociceptive responses of rats following a subcutaneous injection of formalin into the plantar surface of the hind paw, we delivered antisense oligonucleotides (ODNs) against mGluR1 into the rat lumbar spinal cord (L3-L5) intrathecally using an HVJ-liposome-mediated gene transfer method. Rats treated with a single injection of mGluR1 antisense ODNs into the intrathecal space of the lumbar spinal cord showed a marked reduction of the early-sustained phase of formalin-induced nociceptive responses, but not of their acute phase. The reduction of nociceptive behavioral responses became apparent at day 2 after the antisense treatment and lasted for 2 days. This corresponded to a long-lasting down-regulation (46%) of mGluR1 expression in the lumbar cord. This down-regulated mGluR1 was observed at day 2 and persisted until day 4 after the intrathecal infusion of mGluR1 antisense ODN. In contrast, rats treated with mGluR1 sense or mismatch ODNs showed none of these changes. These results suggest that mGluR1 may play a crucial role in the sustained nociception of formalin-induced behavioral responses.