Effect of genetic deletion of the vanilloid receptor TRPV1 on the expression of Substance P in sensory neurons of mice with adjuvant-induced arthritis

Willcockson, Helen H.; Chen, Yong; Han, Ji Eun; Valtschanoff, Juli G.

doi:10.1016/j.npep.2010.02.003

Cited by 6 publications

(4 citation statements)

References 58 publications

(60 reference statements)

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“…SP mediates chondrocyte differentiation in cell cultures ( Millward-Sadler et al, 2003 ) and vasodilation in arthritic mice ( Keeble et al, 2005 ) through the NK1 receptor. SP-like immunoreactivity was shown to increase in the primary sensory neurons of dorsal root ganglia (DRG) of arthritic mice ( Willcockson et al, 2010 ), but the number of sensory nerve fibers of the arthritic joint capsule, that are the main sources of SP, decreased ( Buma et al, 2000 ). Since SP and HK-1 cannot be differentiated by immunological methods, it is possible that these immunohistochemistry data referred (at least partially) to HK-1 expression.…”

Section: Discussionmentioning

confidence: 99%

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

et al. 2021

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The tachykinin hemokinin-1 (HK-1) is involved in immune cell development and inflammation, but little is known about its function in pain. It acts through the NK1 tachykinin receptor, but several effects are mediated by a yet unidentified target. Therefore, we investigated the role and mechanism of action of HK-1 in arthritis models of distinct mechanisms with special emphasis on pain. Arthritis was induced by i.p. K/BxN serum (passive transfer of inflammatory cytokines, autoantibodies), intra-articular mast cell tryptase or Complete Freund’s Adjuvant (CFA, active immunization) in wild type, HK-1- and NK1-deficient mice. Mechanical- and heat hyperalgesia determined by dynamic plantar esthesiometry and increasing temperature hot plate, respectively, swelling measured by plethysmometry or micrometry were significantly reduced in HK-1-deleted, but not NK1-deficient mice in all models. K/BxN serum-induced histopathological changes (day 14) were also decreased, but early myeloperoxidase activity detected by luminescent in vivo imaging increased in HK-1-deleted mice similarly to the CFA model. However, vasodilation and plasma protein extravasation determined by laser Speckle and fluorescent imaging, respectively, were not altered by HK-1 deficiency in any models. HK-1 induced Ca2+-influx in primary sensory neurons, which was also seen in NK1-deficient cells and after pertussis toxin-pretreatment, but not in extracellular Ca2+-free medium. These are the first results showing that HK-1 mediates arthritic pain and cellular, but not vascular inflammatory mechanisms, independently of NK1 activation. HK-1 activates primary sensory neurons presumably via Ca2+ channel-linked receptor. Identifying its target opens new directions to understand joint pain leading to novel therapeutic opportunities.

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Section: Discussionmentioning

confidence: 99%

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

et al. 2021

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“…Indeed, SP was found to be expressed on pruriceptive neurons together with TRPV1 or TRPA1 channels (Sun and Chen, 2007;Imamachi et al, 2009;Liu et al, 2009;Wilson et al, 2013). SP release may occur at both peripheral and central levels, as TRPV1 activation can cause its release at both sites and FK888 was suggested to cross the BBB (Rudd et al, 1999;Willcockson et al, 2010;Steagall et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase-Activated Receptor-4 in Mice

Patrício

Costa

Figueiredo

et al. 2015

Journal of Investigative Dermatology

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A role for proteinase-activated receptor-4 (PAR-4) was recently suggested in itch sensation. Here, we investigated the mechanisms underlying the pruriceptive actions of the selective PAR-4 agonist AYPGKF-NH2 (AYP) in mice. Dorsal intradermal (i.d.) administration of AYP elicited intense scratching behavior in mice, which was prevented by the selective PAR-4 antagonist (pepducin P4pal-10). PAR-4 was found to be coexpressed in 32% of tryptase-positive skin mast cells, and AYP caused a 2-fold increase in mast cell degranulation. However, neither the treatment with cromolyn nor the deficiency of mast cells (WBB6F1-Kit(W/Wv) mice) was able to affect AYP-induced itch. PAR-4 was also found on gastrin-releasing peptide (GRP)-positive neurons (pruriceptive fibers), and AYP-induced itch was reduced by the selective GRP receptor antagonist RC-3095. In addition, AYP evoked calcium influx in ∼1.5% of cultured DRG neurons also sensitive to TRPV1 (capsaicin) and/or TRPA1 (AITC) agonists. Importantly, AYP-induced itch was reduced by treatment with either the selective TRPV1 (SB366791), TRPA1 (HC-030031), or NK1 (FK888) receptor antagonists. However, genetic loss of TRPV1, but not of TRPA1, diminished AYP-induced calcium influx in DRG neurons and the scratching behavior in mice. These findings provide evidence that PAR-4 activation by AYP causes pruriceptive itch in mice via a TRPV1/TRPA1-dependent mechanism.

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“…TRPV1 activation in vivo has been associated with a number of different pathological pain states such as diabetic neuropathy [32], irritable bowel syndrome [33] and inflammatory arthritis [34][35][36]. TRPV1 is thought to contribute to hyperalgesic responses via the peripheral release of substances that might sensitize sensory neurones to other physical, thermal and chemical stimuli such as CGRP [21].…”

Section: Trpv1 Backgroundmentioning

confidence: 99%

TRPV1 antagonists in the treatment of osteoarthritis pain

Kelly¹

2015

International Journal of Clinical Rheumatology

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Pain is the dominant symptom of osteoarthritis (OA) and available analgesic treatments offer inadequate pain relief. The capsaicin receptor, TRPV1 is considered to be a promising analgesic target. TRPV1 is expressed in multiple cell types of the joint. A variant of the TRPV1 gene is associated with the risk of developing symptomatic OA and synovial TRPV1 expression is increased in OA patients undergoing total joint replacement. Potent and selective small molecule TRPV1 antagonists have analgesic effects in preclinical models of OA highlighting the potential utility of TRPV1 antagonists in OA pain management. However, use of these compounds is associated with serious on-target-mediated side effects and analgesic efficacy in OA patients in clinical trials remains to be proven. This review article will discuss recent findings in this area and explore the potential utility of TRPV1 antagonists in the treatment of OA pain. Targeting TRPV1 in the treatment of OA painThere is now a significant body of evidence supporting targeting TRPV1), for the treatment of OA pain [7][8][9][10]. The relevance of TRPV1 to OA pain was highlighted by a recent human genetic study that discovered polymorphisms in the TRPV1 gene associated with symptomatic knee OA [11]. Persistent activation of TRPV1 by the agonist capsaicin causes TRPV1 desensitization and inactivation of TRPV1 expressing sensory neurones. These effects account for why TRPV1 agonists can produce paradoxical analgesia. Topical capsaicin is more effective than placebo for a 50% reduction in pain with a number needed to treat of 8.1 [5]. However, the use of topical capsaicin is associated with increased local adverse events and withdrawals due to these events [12]. The TRPV1 agonist 4975 (Adlea™) developed by Anesiva has been shown to cause a reduction in pain scores with no safety concerns following a single intra-articular injection in end-stage OA patients [13]. A recent Phase II clinical trial demonstrated analgesic efficacy of topic administration of civamide (cis isomer of capsaicin) in patients with knee OA pain [14] and has been approved for topical treatment as a 0.075% cream for the relief of pain in OA patients [14]. Qutenza ® an 8% capsaicin patch is indicated for the management of neuropathic pain associated with postherpetic neuralgia. The long-term analgesic efficacy of topical capsaicin cream in the treatment of knee OA pain [12] and of a capsaicin patch in postherpatic neuralgia provides clear evidence that the blockade of TRPV1 expressing nociceptive afferents at the periphery is a useful strategy to treat chronic pain, although this does not necessarily inform us of the role of TRPV1 itself. The relatively low effectiveness of capsaicin cream and the need to reapply, along with the associated skin irritation has limited civamides' use. Despite this, TRPV1 remains a potential target for OA pain treatment with accumulating preclinical data suggesting that TRPV1 has an important role in the maintenance of established OA pain [7][8][9][10]15]. Several pharma...

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Effect of genetic deletion of the vanilloid receptor TRPV1 on the expression of Substance P in sensory neurons of mice with adjuvant-induced arthritis

Cited by 6 publications

References 58 publications

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

Hemokinin-1 as a Mediator of Arthritis-Related Pain via Direct Activation of Primary Sensory Neurons

Mechanisms Underlying the Scratching Behavior Induced by the Activation of Proteinase-Activated Receptor-4 in Mice

TRPV1 antagonists in the treatment of osteoarthritis pain

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