Resolvin D1 reverses chronic pancreatitis-induced mechanical allodynia, phosphorylation of NMDA receptors, and cytokines expression in the thoracic spinal dorsal horn

Abstract

Background: We previously reported that immune activation in the spinal dorsal horn contributes to pain induced by chronic pancreatitis (CP). Targeting immune response in the CNS may provide effective treatments for CP-induced pain. Recent findings demonstrate that resolvin D1 (RvD1) can potently dampen inflammatory pain. We hypothesized that intrathecal injection of RvD1 may inhibit pain of CP. Methods: Rat CP model was built through intrapancreatic infusion of trinitrobenzene sulfonic acid (TNBS). All the rats were divided into three groups: TNBS, sham, and naïve controls and were further divided for intrathecal RvD1 administration. Pain behavior of rats was tested with von Frey filaments. Anxiety-like behavior and free locomotor and exploration of rats were evaluated by open field test and elevated plus maze. Pancreatic histology was evaluated with hematoxylin and eosin staining. Phosphorylation of NMDA receptor and expression of inflammatory cytokines were examined with Western blot, real-time RT-PCR and ELISA. Results: Behavioral study indicated that compared to the vehicle control, RvD1 (100 ng/kg) significantly decreased TNBS-induced mechanical allodynia at 2 h after administration (response frequencies: 49.2 ± 3.7% vs 71.3 ± 6.1%), and this effect was dose-dependent. Neither CP nor RvD1 treatment could affect anxiety-like behavior. CP or RvD1 treatment could not affect free locomotor and exploration of rats. Western blot analysis showed that compared with that of naïve group, phosphorylated NR1 (pNR1) and pNR2B in TNBS rats were significantly increased in the spinal cord (pNR1: 3.87±0.31 folds of naïve control, pNR2B: 4.17 ± 0.24 folds of naïve control). Compared to vehicle control, 10 ng/kg of RvD1 could significantly block expressions of pNR1 (2.21 ± 0.26 folds of naïve) and pNR2B (3.31 ± 0.34 folds of naïve). Real-time RT-PCR and ELISA data showed that RvD1 (10 ng/kg) but not vehicle could significantly block expressions of TNF-alpha, IL-1beta and IL-6. In addition, RvD1 did not influence pain behavior, NMDA receptor phosphorylation or cytokines production in sham-operated rats.

Lipid Mediators in the Resolution of Inflammation

“…Along these lines, RvD1 (100 ng/kg) decreases TNBS-induced mechanical allodynia and blocked cytokine production in spinal dorsal horn (Quan-Xin et al 2012), and RvD2 (0.01-1 ng) prevents formalin-induced pain. As part of the molecular mechanisms, RvD2, RvE1, and RvD1 differentially regulated transient receptor potential (TRP) channels (Park et al 2011).…”

Glutaminase 1 is a potential biomarker for chronic post-surgical pain in the rat dorsal spinal cord using differential proteomics

“…The dorsal spinal cord then acts as an important pain modulation center, as it provides a place for the brainstem descending suppression system to execute its action and also regulates the transmission of nociceptive information through the intermediate neurons (Singh and Tao 2012;Takazawa and MacDermott 2010;Yang and Ma 2011). Many studies have shown that a large amount of pain-associated molecules act in the dorsal spinal cord, especially those associated with nerve pathological pain (Quan-Xin et al 2012;Wei et al 2013;Xie et al 2012;Zhu et al 2013). Besides, various neurotransmitters and neurotransmitter receptors in the dorsal spinal cord could be altered during the nerve pathological pain (Paul et al 2012;Rahman et al 2007;Wan et al 2004).…”

Targeting the D Series Resolvin Receptor System for the Treatment of Osteoarthritis Pain

“…Spinal administration of RvE1 reduced capsaicin‐ and tumor necrosis factor (TNF)–induced spontaneous pain and hypersensitivity in mice and partially attenuated pain behavior in models of neuropathic pain 20. RvD1 and RvE1 can modulate TRPV‐1 and TNF responses in the spinal cord 20, 21, 22 and inhibit phosphorylation of N ‐methyl‐ d ‐aspartate receptors and cytokine expression in the spinal cord in the setting of chronic pancreatitis‐induced pain 23. Thus, both peripheral and spinal mechanisms of action contribute to the inhibitory effects of the resolvins in models of inflammatory and neuropathic pain, with predominant peripheral antiinflammatory mechanisms including inhibition of neutrophil infiltration, edema, and proinflammatory cytokine expression 21.…”