Pain, a critical component of host defense, is one hallmark of the inflammatory response. We therefore hypothesized that pain might be exacerbated by proinflammatory chemokines. To test this hypothesis, CCR1 was cotransfected into human embryonic kidney (HEK)293 cells together with transient receptor potential vanilloid 1 (TRPV1), a cation channel required for certain types of thermal hyperalgesia. In these cells, capsaicin and anandamide induced Ca2+ influx mediated by TRPV1. When CCR1:TRPV1/HEK293 cells were pretreated with CCL3, the sensitivity of TRPV1, as indicated by the Ca2+ influx, was increased ≈3-fold. RT-PCR analysis showed that a spectrum of chemokine and cytokine receptors is expressed in rat dorsal root ganglia (DRG). Immunohistochemical staining of DRG showed that CCR1 is coexpressed with TRPV1 in >85% of small-diameter neurons. CCR1 on DRG neurons was functional, as demonstrated by CCL3-induced Ca2+ ion influx and PKC activation. Pretreatment with CCL3 enhanced the response of DRG neurons to capsaicin or anandamide. This sensitization was inhibited by pertussis toxin, U73122, or chelerythrine chloride, inhibitors of Gi-protein, phospholipase C, and protein kinase C, respectively. Intraplantar injection of mice with CCL3 decreased their hot-plate response latency. That a proinflammatory chemokine, by interacting with its receptor on small-diameter neurons, sensitizes TRPV1 reveals a previously undescribed mechanism of receptor cross-sensitization that may contribute to hyperalgesia during inflammation

Introduction The Bone and Joint Monitor Project was developed to quantify the global burden of musculoskeletal conditions and develop strategies for their prevention. Experts within the Monitor Project have worked previously with officers at the World Health Organization (WHO) to estimate morbidity and mortality associated with rheumatic conditions. The present collaboration seeks means of providing additional and more current burden data. Objective To develop recommendations for performing epidemiological studies in sample populations with musculoskeletal conditions and problems, accounting for determinants and consequences to the individual and society. Methods Recommendations have been developed identifying the most relevant domains for measuring and monitoring the various musculoskeletal conditions by review of epidemiological data on occurrence, determinants and outcomes, and by expert opinion. Instruments that measure these domains were reviewed. Results The domains recommended follow the principles of the WHO International Classification of Functioning, Disability and Health [1,2], and consider: health condition; body function and structure; activity limitation; participation restriction; personal and environmental contextual factors; and, in addition, the resource utilisation and social consequences. The musculoskeletal conditions and problems considered were osteoarthitis, inflammatory arthritis, osteoporosis, spinal problems, musculoskeletal trauma and injuries, and musculoskeletal pain with restricted activity. The selection of indicators for each domain considered the feasibility of their use in a health interview survey (HIS), a health examination survey (HES), a register or a clinical study. Consensus on case definition was reached depending on the study methodology. For example, osteoporosis defined by bone densitometry cannot be ascertained in an HIS, whereas the outcome of osteoporosis (i.e. fragility fracture) can be. Osteoarthitis can be identified as joint pain in an HIS but the preferred definition is pain with X-ray changes and can only be ascertained in an HES. Previously validated generic and disease-specific instruments have been identified that include indicators for all or most of the recommended domains for the consequences of the different conditions and problems. The indicators of the domains for resource utilisation and social consequences and feasibility for collection will vary in different socioeconomic and geographic areas. Guidance on sampling methods is also being developed. Conclusions The comparability of data collected across the globe will improve by the application of agreed upon indicators that consider key domains for the different musculoskeletal conditions and problems in epidemiological studies conducted in different populations.