Interleukin-1αβ gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain

Honoré, Prisca; Wade, Carrie L.; Zhong, Chengmin; Harris, Richard R.; Wu, Cong; Ghayur, Tariq; Iwakura, Yoichiro; Decker, Michael; Faltynek, Connie R.; Sullivan, James P.; Jarvis, Michael F.

doi:10.1016/j.bbr.2005.09.024

Cited by 108 publications

(71 citation statements)

References 29 publications

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“…In a collagen monoclonal antibody model of arthritis, P2X7(−/−) mice also show a decreased incidence and severity of arthritis as compared to wild-type control mice [58]. P2X7(−/−) mice also show reduced nociceptive sensitivity in inflammatory and neuropathic pain states compared to wild-type controls and this phenotype is consistent with the antinociceptive phenotype of mice lacking both isoforms of IL-1 (IL-1α and IL-1β) [59][60][61].…”

Section: P2x4 Receptorssupporting

confidence: 60%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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Enhanced sensitivity to noxious stimuli and the perception of non-noxious stimuli as painful are hallmark sensory perturbations associated with chronic pain. It is now appreciated that ATP, through its actions as an excitatory neurotransmitter, plays a prominent role in the initiation and maintenance of chronic pain states. Mechanistically, the ability of ATP to drive nociceptive sensitivity is mediated through direct interactions at neuronal P2X3 and P2X2/3 receptors. Extracellular ATP also activates P2X4, P2X7, and several P2Y receptors on glial cells within the spinal cord, which leads to a heightened state of neural-glial cell interaction in ongoing pain states. Following the molecular identification of the P2 receptor superfamilies, selective small molecule antagonists for several P2 receptor subtypes were identified, which have been useful for investigating the role of specific P2X receptors in preclinical chronic pain models. More recently, several P2X receptor antagonists have advanced into clinical trials for inflammation and pain. The development of orally bioavailable blockers for ion channels, including the P2X receptors, has been traditionally difficult due to the necessity of combining requirements for target potency and selectivity with suitable absorption distribution, metabolism, and elimination properties. Recent studies on the physicochemical properties of marketed orally bioavailable drugs, have identified several parameters that appear critical for increasing the probability of achieving suitable bioavailability, central nervous system exposure, and acceptable safety necessary for clinical efficacy. This review provides an overview of the antinociceptive pharmacology of P2X receptor antagonists and the chemical diversity and drug-like properties for emerging antagonists of P2X3, P2X2/3, P2X4, and P2X7 receptors. Keywords

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Section: P2x4 Receptorssupporting

confidence: 60%

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

Gum

Wakefield

Jarvis

2011

Purinergic Signalling

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“…Similar to the nociceptive phenotype of mice lacking P2X 7 receptors or lacking both isoforms of IL-1 (Honore et al, 2006), systemic administration of A-740003 produced dose-dependent antinociceptive effects in models of neuropathic pain and inflammatory pain. A-740003 was particularly potent at reducing mechanical allodynia observed 2 weeks following L 5 /L 6 nerve ligation.…”

Section: Discussionmentioning

confidence: 87%

A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X₇Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat

Honoré

Donnelly‐Roberts

Namovic

et al. 2006

J Pharmacol Exp Ther

370

301

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ATP-sensitive P2X 7 receptors are localized on cells of immunological origin including glial cells in the central nervous system. Activation of P2X 7 receptors leads to rapid changes in intracellular calcium concentrations, release of the proinflammatory cytokine interleukin-1␤ (IL-1␤), and following prolonged agonist exposure, cytolytic plasma membrane pore formation. P2X 7 knockout mice show reduced inflammation as well as decreased nociceptive sensitivity following peripheral nerve injury. A-740003 (N-(1-{[(cyanoimino)(5-quinolinylamino) methyl] amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide) is a novel competitive antagonist of P2X 7 receptors (IC 50 values ϭ 40 nM for human and 18 nM for rat) as measured by agonist-stimulated changes in intracellular calcium concentrations. A-740003 showed weak or no activity (IC 50 Ͼ 10 M) at other P2 receptors and an array of other neurotransmitter and peptide receptors, ion channels, reuptake sites, and enzymes.A-740003 potently blocked agonist-evoked IL-1␤ release (IC 50 ϭ 156 nM) and pore formation (IC 50 ϭ 92 nM) in differentiated human THP-1 cells. Systemic administration of A-740003 produced dose-dependent antinociception in a spinal nerve ligation model (ED 50 ϭ 19 mg/kg i.p.) in the rat. A-740003 also attenuated tactile allodynia in two other models of neuropathic pain, chronic constriction injury of the sciatic nerve and vincristine-induced neuropathy. In addition, A-740003 effectively reduced thermal hyperalgesia observed following intraplantar administration of carrageenan or complete Freund's adjuvant (ED 50 ϭ 38 -54 mg/kg i.p.). A-740003 was ineffective in attenuating acute thermal nociception in normal rats and did not alter motor performance at analgesic doses. These data demonstrate that selective blockade of P2X 7 receptors in vivo produces significant antinociception in animal models of neuropathic and inflammatory pain.

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“…Although a few reports addressed effects of antiinflammatory cytokines (26,27), the majority of studies have concentrated on dampening of immune responses in neuropathy. Thus, deletion of IL-6, IL-1α, and IL-1β or chemokine receptor (CCR2) genes, anti-TNF treatments, and depletion of immune cells were reported to attenuate experimental neuropathic pain (1,2,21,22,24,(28)(29)(30)(31). These studies clearly point to the conclusion that neuroimmune interactions are predominantly detrimental, leading to the generation of pain associated with nerve damage.…”

Section: Introductionmentioning

confidence: 93%

“…This has been attributed to lower levels of inflammatory cytokines or chemokines activating sensory neurons (1,2,21,22). Blockade of TNF production or of IL-1 receptors and deletion of either IL-6, IL-1α, and IL-1β or CCR2 receptor genes were reported to decrease experimental neuropathic pain (1,28,30,31). Nevertheless, other studies reported that macrophages and lymphocytes can stimulate tissue repair and motor function recovery or decrease hypersensitivity after peripheral nerve or spinal cord injury, mostly by removing tissue debris and producing neurotrophins or antiinflammatory cytokines (27,(44)(45)(46).…”

Section: Figurementioning

confidence: 99%

Immune cell–derived opioids protect against neuropathic pain in mice

Łabuz¹,

Schmidt²,

Schreiter³

et al. 2009

J. Clin. Invest.

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The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as β-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies. IntroductionWithin inflamed tissues, a plethora of molecules such as protons, adenosine triphosphate, glutamate, neuropeptides (e.g., calcitonin gene-related peptide [CGRP], substance P), prostaglandins, bradykinin, cytokines, and chemokines can induce pain (1, 2). Concurrently, however, endogenous counterregulatory mechanisms are mounted. It has been established that somatic inflammatory (e.g., postoperative and arthritic) pain can be effectively controlled by the immune system, in both animals and humans (3,4). This is mediated by extravasating leukocytes, which produce and liberate opioid peptides in inflamed tissues. The released opioids bind to opioid receptors on peripheral sensory neurons, resulting in the inhibition of noxious impulse propagation (5-17). Such effects are particularly interesting because they occur directly in peripheral tissues and, therefore, are free of side effects such as nausea, depression of breathing, cognitive impairment, dependence, and addiction mediated by opioid receptors in the CNS (3).Neuropathic pain is a common consequence of nerve injuries caused by trauma such as amputation, entrapment, or compression. It is characterized by persistent burning or shooting sensations and heightened responses to normally noxious (hyperalgesia) and innocuous stimuli (allodynia). Despite increasing efforts, such pain remains poorly controlled, severely impacting patients ' well-being (18-20), which makes new therapeutic approaches highly desirable. Research over the last decade has provided evidence on the association of traumatic peripheral nerve injuries with inflammatory reactions mobilizing the immune system (1,

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Interleukin-1αβ gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain

Cited by 108 publications

References 29 publications

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X₇Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat

Immune cell–derived opioids protect against neuropathic pain in mice

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Interleukin-1αβ gene-deficient mice show reduced nociceptive sensitivity in models of inflammatory and neuropathic pain but not post-operative pain

Cited by 108 publications

References 29 publications

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

P2X receptor antagonists for pain management: examination of binding and physicochemical properties

A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X7Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat

Immune cell–derived opioids protect against neuropathic pain in mice

Contact Info

Product

Resources

About

A-740003 [N-(1-{[(Cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a Novel and Selective P2X₇Receptor Antagonist, Dose-Dependently Reduces Neuropathic Pain in the Rat