Analgesic effect of gastrin-releasing peptide in the dorsal horn

Itch and pain are both unpleasant, but they are discrete sensations. Both of these sensations are transmitted by C-fibers and processed in laminae I-II of the dorsal horn. To examine whether pruriception modulates pain, we first confirmed the activation of cells in the itch-related circuits that were positive for gastrin-releasing peptide (GRP) and GRP receptor (GRPR) using a paw formalin injection model. This pain model with typical biphasic pain behavior increased c-Fos but did not affect the expressions of GRP and GRPR mRNAs in the dorsal horn. Using c-Fos expression as a marker for activated cells, we confirmed that formalin injection increased the number of cells double-labeled for c-Fos and GRP or GRPR in the dorsal horn. The emergence of these neurons indicates the activation of itch-related circuits by acute pain signals. The effect of an antagonist for a GRPR was examined in the paw formalin injection model. Intrathecal chronic antagonization of spinal GRPR enhanced the onset of phase II of paw formalin injection-induced pain behavior. Exogenous intrathecal GRP infusion to the paw-formalin injection model not only showed significant reduction of pain behavior but also increased c-Fos in the inhibitory neurons in the dorsal horn. The anti-nociceptive effect of spinal GRP infusion was observed in the peripheral inflammation model (complete Freund's adjuvant injection model). In this study we suggest that painful stimuli activated itch-related neuronal circuits and uncovered the spinal activation of the itch-induced analgesic effect on acute and established inflammatory pain.