bromochloroacetic-acid and Complex-Regional-Pain-Syndromes

Tibia fracture followed by limb immobilization in rats evokes nociceptive and vascular changes resembling complex regional pain syndrome type I (CRPS I). Previously we observed that substance P (SP) and interleukin-1beta (IL-1beta) signaling contribute to chronic regional nociceptive sensitization in this model. It is known that inflammasome multi-protein complexes containing caspase-1 and NALP1 are involved in the activation of the IL-1beta family of pro-nociceptive cytokines expressed in skin and other tissues. Therefore, we hypothesized that SP activated inflammasomes might contribute to mechanical allodynia after fracture. Using this model we observed that: (1) inflammasome components and products NALP1, caspase-1, IL-1beta and IL-18 were present in low levels in normal skin, but expression of all these was strongly up-regulated after fracture, (2) NALP1, caspase-1 and IL-1beta were co-expressed in keratinocytes, and the number of NALP1, caspase-1, and IL-1beta positive cells dramatically increased at 4 weeks post-fracture, (3) LY303870, an NK1 receptor antagonist, effectively blocked fracture-induced up-regulation of activated inflammasome components and cytokines, (4) IL-1beta and IL-18 intraplantar injection induced mechanical allodynia in normal rats, and (5) both a selective caspase-1 inhibitor and an IL-1 receptor antagonist attenuated fracture-induced hindpaw mechanical allodynia. Collectively, these data suggest that NALP1 containing inflammasomes activated by NK1 receptors are expressed in keratinocytes and contribute to post-traumatic regional nociceptive sensitization. These findings highlight the possible importance of neuro-cutaneous signaling and innate immunity mechanisms in the development of CRPS.

Topics: Animals; Antirheumatic Agents; Caspase 1; Caspases, Initiator; Complex Regional Pain Syndromes; Cytokines; Enzyme-Linked Immunosorbent Assay; Fractures, Bone; Gene Expression Regulation; Indoles; Interleukin 1 Receptor Antagonist Protein; Keratinocytes; Keratins; Male; Nerve Growth Factor; Nerve Tissue Proteins; Pain Measurement; Pain Threshold; Physical Stimulation; Piperidines; Rats; Rats, Sprague-Dawley; Signal Transduction; Substance P; Time Factors