Nociception is initiated at the site of insult by primary afferent nerve endings responding to the inflamed tissue environment. At the site of injury or inflammation, numerous mediators including cytokines and chemokines are released from infiltrated or resident leukocytes. Evidence is now accumulating that suggests these mediators are capable of stimulating primary afferent neurons and consequently participate in nociceptive transmission. Endothelial cells are critically involved in the process of leukocyte recruitment and progression of inflammation. To understand how these molecules act on the initial steps of the nociceptive circuit and signaling between the peripheral nervous system and the CNS and immune system, we examined the expression profile of cytokines and endothelial-related genes in inflamed tissues and corresponding sensory ganglia in rats injected with carrageenan into the hind paw. Use of two focused microarrays showed elevations of forty-two cytokine- and endothelial cell-related transcripts in the inflamed paw including Scya2, TNFα, Il6 and Il-1β, which are suggested to be involved in pain transmission at the DRG level. Analysis of cytokine related genes in DRG by RT-PCR and in situ hybridization revealed that Scya2 mRNA which codes for monocyte chemoattractant protein-1 (MCP-1/CCL2), the transcript most highly increased in inflamed peripheral tissue, was also up-regulated in DRG in our rat model of peripheral inflammation. Up-regulation of Scya2 in DRG also occurred after direct C-fiber stimulation with intraplantar administration of resiniferatoxin, suggesting that up-regulation is dependent on increased nociceptive afferent activity. Consistent with this observation, in situ hybridization histochemistry shows that Scya2 is expressed in small diameter neurons, some which co-express the vanilloid receptor. In cultured DRG neurons, addition of MCP-1 to the medium induces up-regulation of COX2 expression. Among many functions reported for MCP-1, our results are consistent with the involment of MCP-1, derived from DRG neurons, in inflammatory pain.