Characterization of the acute and persistent pain state present in K/BxN serum transfer arthritis

Department of Pharmacology, University of California, San Diego, La Jolla, CA, USA.
Pain (Impact Factor: 5.21). 11/2010; 151(2):394-403. DOI: 10.1016/j.pain.2010.07.030
Source: PubMed

ABSTRACT

Rheumatoid arthritis (RA) is a chronic autoimmune arthritis that affects approximately 1% of the population. Synovial inflammation cannot fully explain the level of pain reported by patients and facilitation of pain processing at the spinal level has been implicated. We characterized the K/BxN serum transfer arthritis model as a model of joint inflammation-induced pain and examined pharmacologic responsiveness and spinal glia activation. Mechanical allodynia developed congruently with joint swelling. Surprisingly, allodynia persisted after resolution of inflammation. At the peak of joint inflammation (days 4-10), hypersensitivity was attenuated with i.p. etanercept, gabapentin, and ketorolac. Following resolution of synovial inflammation (days 19-23), only gabapentin relieved allodynia. The superficial dorsal horn of arthritic mice displayed increased staining of microglia at early and late time points, but astrocyte staining increased only during the inflammatory phase. ATF3, a marker of nerve injury, was significantly increased in the lumbar dorsal root ganglia during the late phase (day 28). Hence, serum transfer in the K/BxN serum transfer arthritis model produces a persistent pain state, where the allodynia during the inflammatory state is attenuated by TNF and prostaglandin inhibitors, and the pharmacology and histochemistry data suggest a transition from an inflammatory state to a state that resembles a neuropathic condition over time. Therefore, the K/BxN serum transfer model represents a multifaceted model for studies exploring pain mechanisms in conditions of joint inflammation and may serve as a platform for exploring novel treatment strategies for pain in human arthritic conditions.

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Available from: Tony Yaksh, Jan 16, 2014
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    • "These findings indicate that pain signalling manifested by changes in mechanical thresholds in the early and late phases of both models are driven by different mechanisms. The presumed aversive nature of the early and late (post-inflammatory) phases is predicated on the hypothesis that paw withdrawal reflects escape from an aversive state evoked by the low intensity tactile stimulus (Inglis et al., 2007; Christianson et al., 2010; Bas et al., 2012). Accordingly, simple relief of that ongoing state would be considered to possess a positive reinforcing component, which would support behaviours generating that relief. "
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    ABSTRACT: Background: Glucose-6-phosphate isomerase and collagen type II antibody-induced arthritis models (K/BxN and CAIA, respectively) have an inflammatory and a post-inflammatory phase. Both phases display robust tactile allodynia. In previous work, inflammatory phase allodynia was reversed by gabapentin and ketorolac, whereas in late phase only gabapentin was effective. Here, we sought to determine if the effects of these two drugs during the early and late phases of the two arthritis models were observed in the conditioned place preference (CPP) paradigm, indicating a differential drug effect on the aversive state. Methods: Male C57BL/6 mice received K/BxN serum intraperitoneally, while male BALB/c mice received collagen type II antibody cocktail intravenously. After onset of inflammation and allodynia, we assessed effects of i.p. gabapentin (100 mg/kg) or ketorolac (15 mg/kg) using a CPP paradigm: 2 days adaptation, 2 days conditioning (vehicle in morning and drug in afternoon), preference testing on day 5. Results: Consistent with the effects upon allodynia, both gabapentin and ketorolac produced a preference for the drug-paired compartment in the early phase of the K/BxN model, while gabapentin, but not ketorolac, resulted in a place preference during late phase. In the CAIA model, consistent with differential effects upon allodynia, gabapentin produced a preference in the early phase and a trend in the late phase, whereas ketorolac was ineffective at either time. Conclusions: CPP validated the aversive state in the inflammatory and post-inflammatory phases of the K/BxN and CAIA arthritis models and correspondence between the anti-hyperpathic pharmacology as defined by thresholds and CPP.
    Full-text · Article · Oct 2015 · European journal of pain (London, England)
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    • "However, descriptors that are more characteristic of neuropathic pain such as "burning" or "shooting" are also common for RA pain, indicating possible components of nerve damage (Roche et al., 2003; Sokka, 2011). While analgesic drugs such as gabapentin and buprenorphine attenuate the mechanical hypersensitivity during both the inflammatory and postinflammatory phases in our experimental models of RA, the cyclooxygenase (COX) inhibitors diclofenac and ketorolac are antinociceptive only during the inflammatory phase (Christianson et al., 2010; Bas et al., 2012). This Figure 6. "

    Full-text · Dataset · May 2015
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    • "However, descriptors that are more characteristic of neuropathic pain such as "burning" or "shooting" are also common for RA pain, indicating possible components of nerve damage (Roche et al., 2003; Sokka, 2011). While analgesic drugs such as gabapentin and buprenorphine attenuate the mechanical hypersensitivity during both the inflammatory and postinflammatory phases in our experimental models of RA, the cyclooxygenase (COX) inhibitors diclofenac and ketorolac are antinociceptive only during the inflammatory phase (Christianson et al., 2010; Bas et al., 2012). This Figure 6. "
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    ABSTRACT: The mechanisms underlying rheumatoid arthritis (RA)-induced pain are still not fully elucidated, and accumulating data indicate that peripheral inflammation is not the only factor driving pain in these patients. The focus of our work is to investigate the molecular basis for long-term alterations in nociceptive pathways induced by polyarthritis using the collagen antibody-induced arthritis (CAIA) mouse model. In this model, mechanical hypersensitivity outlasts the joint inflammation by weeks. Here we examined expression levels of neuropeptides, ion channels and nerve injury markers associated with neuropathic and/or inflammatory pain in dorsal root ganglia (DRGs) and spinal cord both during the peak of inflammation (day 15) and when the inflammation has resolved but the hypersensitivity persists (days 45-47). No apparent differences were observed in substance P, calcitonin gene-related peptide or neuropeptide Y protein expression in DRGs and spinal cord of CAIA mice. However, the neuropeptide galanin, the ATP-gated ion channel P2X3 and calcium channel subunit α2δ1 were significantly increased in the CAIA DRGs as compared to controls, both 15 and 47 days after induction of arthritis. On day 15 there was an increase in expression of two factors associated with nerve injury and cell stress, activating transcription factor-3 (ATF3) and growth-associated protein 43 (GAP43) in DRGs, whereby the latter was still dramatically upregulated after 47 days. In conclusion, this study suggests that long-term joint inflammation has an impact on DRG neurons that resembles both inflammation and nerve-injury induced pain states. Thus, antibody-driven inflammation generates a pain state with a unique neurochemical profile. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jan 2015 · The Journal of Comparative Neurology
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