The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome

Li, Wen-Wu; Guo, Tian-Zhi; Liang, Deyong; Shi, Xiaoyou; Wei, Tzuping; Kingery, Wade S.; Clark, J. David

doi:10.1016/j.pain.2009.09.032

« Previous Next »PAIN
Volume 147, Issue 1 , Pages 277-286, 15 December 2009

The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome

Wen-Wu Li
- Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
Tian-Zhi Guo
- Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
Deyong Liang
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
Xiaoyou Shi
- Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
Tzuping Wei
- Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
Wade S. Kingery
- Physical Medicine and Rehabilitation Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, USA
J. David Clark
- Anesthesiology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
- Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA
- Corresponding author. Address: Department of Anesthesiology (112A), Veterans Affairs Palo Alto Health Care System, 3801 Miranda Ave., Palo Alto, CA 94304, USA. Tel.: +1 650 493 5000x67184; fax: +1 650 852 3423.

Received 24 July 2009; received in revised form 14 September 2009; accepted 30 September 2009. published online 23 October 2009.

Abstract

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-1β (IL-1β) 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-1β 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-1β 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-1β were co-expressed in keratinocytes, and the number of NALP1, caspase-1, and IL-1β positive cells dramatically increased at 4weeks post-fracture, (3) LY303870, an NK1 receptor antagonist, effectively blocked fracture-induced up-regulation of activated inflammasome components and cytokines, (4) IL-1β 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.