A distinct role for transient receptor potential ankyrin 1, in addition to transient receptor potential vanilloid 1, in tumor necrosis factor α-induced inflammatory hyperalgesia and Freund's complete adjuvant-induced monarthritis

Abstract

Objective. To investigate the involvement of transient receptor potential ankyrin 1 (TRPA1) in inflammatory hyperalgesia mediated by tumor necrosis factor ␣ (TNF␣) and joint inflammation.Methods. Mechanical hyperalgesia was assessed in CD1 mice, mice lacking functional TRP vanilloid 1 (TRPV1 ؊/؊ ) or TRPA1 (TRPA1 ؊/؊ ), or respective wildtype (WT) mice. An automated von Frey system was used, following unilateral intraplantar injection of TNF␣ or intraarticular injection of Freund's complete adjuvant (CFA). Knee swelling and histologic changes were determined in mice treated with intraarticular injections of CFA.Results. TNF␣ induced cyclooxygenase-independent bilateral mechanical hyperalgesia in CD1 mice. The selective TRPV1 receptor antagonist SB-366791 had no effect on mechanical hyperalgesia when it was coinjected with TNF␣, but intrathecally administered SB-366791 attenuated bilateral hyperalgesia, indicating the central but not peripheral involvement of TRPV1 receptors. A decrease in pain sensitivity was also observed in TRPV1 ؊/؊ mice. Intraplantar coadministration of the TRPA1 receptor antagonist AP-18 with TNF␣ inhibited bilateral hyperalgesia. Intrathecal treatment with AP-18 also reduced TNF␣-induced hyperalgesia. CFA-induced mechanical hyperalgesia in CD1 mice was attenuated by AP-18 (administered by intraarticular injection 22 hours after the administration of CFA). Furthermore, intraarticular CFA-induced ipsilateral mechanical hyperalgesia was maintained for 3 weeks in TRPA1 WT mice. In contrast, TRPA1 ؊/؊ mice exhibited mechanical hyperalgesia for only 24 hours after receiving CFA.Conclusion. Evidence suggests that endogenous activation of peripheral TRPA1 receptors plays a critical role in the development of TNF␣-induced mechanical hyperalgesia and in sustaining the mechanical hyperalgesia observed after intraaarticular injection of CFA. These results suggest that blockade of TRPA1 receptors may be beneficial in reducing the chronic pain associated with arthritis.Sensory nerves consisting of C and A␦ nerve fibers innervate joints and skin and are often located in close association with blood vessels (1-3). Nerve stimulation in inflamed joints is considered to play a primary role in arthritis-related pain, and sensory afferent nerves have been located in joints, where they terminate in subsynovial connective tissue (4). Certain members of the transient receptor potential (TRP) receptor family, which are expressed on sensory nerves, are involved as key molecular integrators in the initiation and maintenance of joint pain, although the precise mechanisms involved are unclear (5,6).

4-Oxo-2-nonenal (4-ONE): Evidence of Transient Receptor Potential Ankyrin 1-Dependent and -Independent Nociceptive and Vasoactive Responses In Vivo

“…In their studies, coinjection with 1 mM AP18 inhibited the acute nocifensive behavior induced by cinnamaldehyde during the first 5 min after injection (Petrus et al, 2007), and AP18 partially blocked the early phase of bradykinin-evoked mechanical hyperalgesia, which is thought to be mediated by activation of TRPA1 (Petrus et al, 2007;Wang et al, 2008). This indicates that AP18 has a short half-life in vivo; however, intraplantar injections of 1 mM AP18 that were given 24 h after complete Freund's adjuvant treatment were able to reverse complete Freund's adjuvant-induced mechanical hyperalgesia at 1 and 2 h postinjection (Petrus et al, 2007;Fernandes et al, 2010). In the present study, TRPA1 KO mice did not develop 4-ONE-induced mechanical hyperalgesia at 0.5 h postinjection although mechanical hyperalgesia was observed from 1 to 4 h postinjection in TRPA1 KO mice.…”

“…A significant reduction in paw withdrawal thresholds (g) compared with baseline values was defined as mechanical hyperalgesia. In some experiments, 4-(4-chlorophenyl)-3-methyl-3-buten-2-one oxime (AP18) (25 nmol in 25 l of a 1 mM solution; Petrus et al, 2007;Fernandes, et al, 2010), a small-molecule TRPA1 receptor antagonist, was given intraplantarly 15 min before 4-ONE or vehicle injections. The injection pattern was always randomized, and all measurements were carried out by an observer blinded to treatment regimes and genotype of the mice.…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…In addition to enhanced neurotransmitter release, stimulation of TRPV1 is associated with increases in inflammatory mediators contributing to joint inflammation (47). A recent study found that tumor necrosis factor-alpha (TNF-α)-induced mechanical hyperalgesia in an arthritic model could be blocked by a central, but not peripheral, injection of a TRPV1 antagonist (48). Similarly, interleukin-1 beta (IL-1β) can upregulate TRPV1 expression in arthritic rat DRG neurons, as well as sensitize articular C-fibers (48).…”

“…A recent study found that tumor necrosis factor-alpha (TNF-α)-induced mechanical hyperalgesia in an arthritic model could be blocked by a central, but not peripheral, injection of a TRPV1 antagonist (48). Similarly, interleukin-1 beta (IL-1β) can upregulate TRPV1 expression in arthritic rat DRG neurons, as well as sensitize articular C-fibers (48). Together, these findings indicate a novel link between TRP channels and cytokines in the generation of joint pain through central sensitization (44).…”

Mutagenesis and Temperature-Sensitive Little Machines

“…However, there are deficits in the response to mechanical stimuli [23,43]. Later it was found that like TRPV1 (see below), TRPA1 is actually involved in inflammatory-related hyperalgesia [44,45]. Most likely, this role is given by its activation or modulation by a great variety of chemical agents, including several inflammatory-or cell damage-related molecules.…”