Spontaneous firing in C-fibers and increased mechanical sensitivity in A-fibers of knee joint-associated mechanoreceptive primary afferent neurones during MIA-induced osteoarthritis in the rat

Kelly, Sara; Dunham, James P.; Murray, Fraser; Read, Simon; Donaldson, Lucy F.; Lawson, Sally N.

doi:10.1016/j.joca.2012.01.002

Cited by 53 publications

(61 citation statements)

References 48 publications

(71 reference statements)

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“…During inflammation, sensory neurones innervating joints become sensitized,2, 3, 4, 5 which contributes to the tenderness of arthritic joints 6, 7. The inflammatory milieu contains many mediators, including protons, and early measurements of synovial fluid pH from rheumatoid arthritis (RA) patients found a pH of 7.21, compared with 7.43 in healthy subjects 8.…”

Section: Introductionmentioning

confidence: 99%

Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate

Wright

Husson

et al. 2018

NMR in Biomedicine

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Arthritic conditions are a major source of chronic pain. Furthering our understanding of disease mechanisms creates the opportunity to develop more targeted therapeutics. In rheumatoid arthritis (RA), measurements of pH in human synovial fluid suggest that acidosis occurs, but that this is highly variable between individuals. Here we sought to determine if tissue acidosis occurs in a widely used rodent arthritis model: complete Freund's adjuvant (CFA)‐induced inflammation. CFA robustly evoked paw and ankle swelling, concomitant with worsening clinical scores over time. We used magnetic resonance spectroscopic imaging of hyperpolarized [1‐13C]pyruvate metabolism to demonstrate that CFA induces an increase in the lactate‐to‐pyruvate ratio. This increase is indicative of enhanced glycolysis and an increased lactate concentration, as has been observed in the synovial fluid from RA patients, and which was correlated with acidosis. We also measured the 13CO2/H13CO3 − ratio, in animals injected with hyperpolarized H13CO3 −, to estimate extracellular tissue pH and showed that despite the apparent increase in glycolytic activity in CFA‐induced inflammation there was no accompanying decrease in extracellular pH. The pH was 7.23 ± 0.06 in control paws and 7.32 ± 0.09 in inflamed paws. These results could explain why mice lacking acid‐sensing ion channel subunits 1, 2 and 3 do not display any changes in mechanical or thermal hyperalgesia in CFA‐induced inflammation.

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Section: Introductionmentioning

confidence: 99%

Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate

Wright

Husson

et al. 2018

NMR in Biomedicine

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Section: Preclinical Modeling Of Oa Painmentioning

confidence: 99%

“…Pain behavior appears as early as 1 day post-injection and persists for at least 63 days [59,60,63] and is thought to be driven by both peripheral and central sensitization. Nociceptive C-and Aδ-fibers are sensitized at 14 days following MIA model induction [10, 63,64] indicating peripheral future science group Review Kelly sensitization of joint afferent nociceptors. 28 days following model induction wide dynamic range spinal dorsal horn neuronal responses [65] and himb-limb spinal nociceptive withdrawal reflexes [66] are sensitized to hind paw mechanical stimulation indicating that central nociceptive pathways are also sensitized (i.e., central sensitization).…”

Section: Preclinical Modeling Of Oa Painmentioning

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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“…Спон-танная активность в С-волокнах может вызывать централь-ную сенситизацию и способствовать изменению ноцицеп-ции. Снижение механического порога А-волокон является доказательством периферической основы механической ги-перчувствительности при ОА [21].…”

Section: в статье изложены современные представления о механизмах разunclassified

Current views of the development of pain syndrome mechanisms in patients with osteoarthrosis. Rational pharmacotherapy

Иголкина¹

2014

RJTAO

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Spontaneous firing in C-fibers and increased mechanical sensitivity in A-fibers of knee joint-associated mechanoreceptive primary afferent neurones during MIA-induced osteoarthritis in the rat

Cited by 53 publications

References 48 publications

Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate

Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate

TRPV1 antagonists in the treatment of osteoarthritis pain

Current views of the development of pain syndrome mechanisms in patients with osteoarthrosis. Rational pharmacotherapy

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Spontaneous firing in C-fibers and increased mechanical sensitivity in A-fibers of knee joint-associated mechanoreceptive primary afferent neurones during MIA-induced osteoarthritis in the rat

Cited by 53 publications

References 48 publications

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

Increased hyperpolarized [1‐13C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized 13C‐labelled bicarbonate

TRPV1 antagonists in the treatment of osteoarthritis pain

Current views of the development of pain syndrome mechanisms in patients with osteoarthrosis. Rational pharmacotherapy

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Product

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Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate

Increased hyperpolarized [1‐¹³C] lactate production in a model of joint inflammation is not accompanied by tissue acidosis as assessed using hyperpolarized ¹³C‐labelled bicarbonate