IL-1β signaling is required for mechanical allodynia induced by nerve injury and for the ensuing reduction in spinal cord neuronal GRK2

Low Nociceptor GRK2 Prolongs Prostaglandin E2Hyperalgesia via Biased cAMP Signaling to Epac/Rap1, Protein Kinase Cε, and MEK/ERK

“…Our present results show that GRK2 levels are reduced in small-diameter DRG neurons during carrageenan-induced hyperalgesia. In addition, we described that spinal cord neuronal and microglial GRK2 was reduced in rat or mouse models of neuropathic pain (Kleibeuker et al, 2007(Kleibeuker et al, , 2008Eijkelkamp et al, 2010). It is therefore tempting to speculate that an inflammation-induced decrease in GRK2 levels may contribute to the chronic pain that develops in conditions of chronic inflammation or nerve damage.…”

“…In vivo, the level of GRK2 in leukocytes from patients with autoimmune diseases such as rheumatoid arthritis and multiple sclerosis is decreased, and similar changes in GRK2 expression occur in animals with experimental autoimmune en-cephalomyelitis and adjuvant arthritis (Lombardi et al, 1999;Vroon et al, 2005Vroon et al, , 2006. Moreover, neuropathic pain in animals subjected to nerve ligation is associated with decreased spinal cord neuronal and microglial GRK2 expression, suggesting that GRK2 may contribute to regulation of pain signaling under inflammatory conditions (Kleibeuker et al, 2007(Kleibeuker et al, , 2008Eijkelkamp et al, 2010).…”

“…In view of the fact that inflammation reduces GRK2 from 35 to 50% in various cell types including DRG, we decided to use mice heterozygous for deletion of the GRK2 gene in Na v 1.8 ϩ nociceptors (SNS-GRK2 ϩ/Ϫ mice) and SNS-GRK2 ϩ/ϩ (WT) littermate controls for additional experiments. To address the question whether the increased and prolonged PGE 2 hyperalgesia in GRK2-deficient mice was caused by developmental adaptation to GRK2 deficiency, we also used tamoxifentreated inducible GRK2 ϩ/Ϫ mice compared with GRK2 ϩ/Ϫ mice that have a 40 -60% decrease in GRK2 protein in all cells throughout development (Kleibeuker et al, 2008;Eijkelkamp et al, 2010).…”

Neuroinflammation and Comorbidity of Pain and Depression

“…In recent years, GRK2 has yielded much interest in regards to the pathogenesis of chronic pain. This began with observations that spinal nerve transection decreases spinal GRK2 expression and chronic carageenan-induced hyperalgesia reduces GRK2 levels in the DRG (Kleibeuker et al, 2008;Eijkelkamp et al, 2010b). A number of preclinical studies have demonstrated that low levels of GRK2 prolong mechanical and thermal hyperalgesia in response to a range of stimuli, including epinephrine, and a number of inflammatory mediators, including carageenan, IL-1b, and prostaglandin E 2 (Eijkelkamp et al, 2010a,b;Willemen at al., 2010;Wang et al, 2011).…”

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

“…Glial activation and subsequent release of proinflammatory cytokines, including IL-1␤ in the spinal dorsal horn, have been observed in neuropathic pain induced by peripheral nerve injury (7)(8)(9). Knocking out IL-1␤ receptors reduces behavioral hypersensitivity induced by nerve injury (10,11). Intrathecal administration of IL-1␤ in normal rats enhances both the acute response and the wind-up activity of dorsal horn neurons and increases mechanical allodynia and hyperalgesia (12)(13)(14).…”