Abstract
BackgroundThe effect of cold temperature on arthritis symptoms is unclear. The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor.MethodsMono-arthritis was induced by unilateral intra-articular injection of complete Freund’s adjuvant (CFA) in CD1 mice, and in mice either lacking TRPA1 (TRPA1 KO) or respective wildtypes (WT). Two weeks later, nociception and joint blood flow were measured following exposure to 10 °C (1 h) or room temperature (RT). Primary mechanical hyperalgesia in the knee was measured by pressure application apparatus; secondary mechanical hyperalgesia by automated von Frey system; thermal hyperalgesia by Hargreaves technique, and weight bearing by the incapacitance test. Joint blood flow was recorded by full-field laser perfusion imager (FLPI) and using clearance of 99mTechnetium. Blood flow was assessed after pretreatment with antagonists of either TRPA1 (HC-030031), substance P neurokinin 1 (NK1) receptors (SR140333) or calcitonin gene-related peptide (CGRP) (CGRP8–37). TRPA1, TAC-1 and CGRP mRNA levels were examined in dorsal root ganglia, synovial membrane and patellar cartilage samples.ResultsCold exposure caused bilateral primary mechanical hyperalgesia 2 weeks after CFA injection, in a TRPA1-dependent manner. In animals maintained at RT, clearance techniques and FLPI showed that CFA-treated joints exhibited lower blood flow than saline-treated joints. In cold-exposed animals, this reduction in blood flow disappears, and increased blood flow in the CFA-treated joint is observed using FLPI. Cold-induced increased blood flow in CFA-treated joints was blocked by HC-030031 and not observed in TRPA1 KOs. Cold exposure increased TRPA1 mRNA levels in patellar cartilage, whilst reducing it in synovial membranes from CFA-treated joints.ConclusionsWe provide evidence that environmental cold exposure enhances pain and increases blood flow in a mono-arthritis model. These changes are dependent on TRPA1. Thus, TRPA1 may act locally within the joint to influence blood flow via sensory nerves, in addition to its established nociceptive actions.
Highlights
The effect of cold temperature on arthritis symptoms is unclear
Cold exposure causes bilateral pain sensitivity in knee joints of mice with complete Freund’s adjuvant (CFA)-induced mono-arthritis, in a transient receptor potential ankyrin 1 (TRPA1)-dependent manner The effect of environmental cold on the pain threshold of arthritic mice was evaluated through a range of nociceptive parameters, namely the measurement of primary and secondary mechanical hyperalgesia, thermal hyperalgesia and weight-bearing distribution (Fig. 1)
CFA injection, unilateral secondary mechanical hyperalgesia and bilateral secondary thermal hyperalgesia were observed both in mice maintained at room temperature (RT) and mice exposed to cold (Fig. 1a and b), cold exposure had no effect on secondary measures of pain
Summary
The aim of this study was to investigate how environmental cold affects pain and blood flow in mono-arthritic mice, and examine a role for transient receptor potential ankyrin 1 (TRPA1), a ligand-gated cation channel that can act as a cold sensor. One potential mediator is the transient receptor potential ankyrin 1 (TRPA1) channel, shown to be essential for acute cold hypersensitivity in hindpaw inflammatory models [8,9,10]. The channel is activated by temperatures ranging from 10 °C to 17 °C [12, 13], though its role as a cold sensor in vivo is controversial [14]. We have previously demonstrated that TRPA1 mediates tumour necrosis factor alpha (TNF-α)-induced inflammatory pain by modulating mechanical hyperalgesia via both the central and peripheral nervous systems [16]. TRPA1 plays an important role in noxious mechanosensation in normal, inflamed and osteoarthritic models [17], and we have observed a sustained mechanical hyperalgesia in wild-type (WT) but not TRPA1 knockout (KO) mice with CFA-induced monoarthritis [16]
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