Enduring prevention and transient reduction of postoperative pain by intrathecal resolvin D1

Pain Research Center, Department of Anesthesia, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA.
Pain (Impact Factor: 5.21). 03/2011; 152(3):557-65. DOI: 10.1016/j.pain.2010.11.021
Source: PubMed


Postoperative pain slows surgical recovery, impacting the return of normal function for weeks, months, or longer. Here we report the antihyperalgesic actions of a new compound, resolvin D1 (RvD1), known to reduce inflammation and to suppress pain after peripheral nerve injury, on the acute pain occurring after paw incision and the prolonged pain after skin-muscle retraction. Injection of RvD1 (20-40ng) into the L5-L6 intrathecal space 30minutes before surgery reduces the postincisional primary mechanical hypersensitivity, lowering the peak change by approximately 70% (with 40ng) and reducing the area under the curve (AUC) for the entire 10-day postincisional course by approximately 60%. Intrathecal injection of RvD1 on postoperative day (POD) 1 reduces the hyperalgesia to the same level as that from preoperative injection within a few hours, an effect that persists for the remaining PODs. Tactile allodynia and hyperalgesia following the skin/muscle incision retraction procedure, measured at the maximum values 12 to 14days, is totally prevented by intrathecal RvD1 (40ng) given at POD 2. However, delaying the injection until POD 9 or POD 17 results in RvD1 causing only transient and incomplete reversal of hyperalgesia, lasting for <1day. These findings demonstrate the potent, effective reduction of postoperative pain by intrathecal RvD1 given before or shortly after surgery. The much more limited effect of this compound on retraction-induced pain, when given 1 to 2weeks later, suggests that the receptors or pathways for resolvins are more important in the early than the later stages of postoperative pain. Single intrathecal injections of resolvin D1 in rats before or 1 to 2days after surgery strongly reduce postoperative pain for several weeks.

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    • "Resolvin D1 and Resolvin E1 potently regulate inflammatory pain (Xu et al. 2010), and intrathecal injections of RvD1 in rats reduces postoperative surgical pain (Huang et al. 2011). 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. "
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    ABSTRACT: Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis.
    Cold Spring Harbor perspectives in biology 10/2014; 7(2). DOI:10.1101/cshperspect.a016311 · 8.68 Impact Factor
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    • "The doses of resolvins or pregabalin were determined on the basis of previous publications and pilot experiments (Bento et al., 2011; Huang et al., 2011; Wallin et al., 2002). On the adopted schedules of treatment, none of the lipid mediators elicited any effect per se (data not shown). "
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    ABSTRACT: This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.
    Neuropharmacology 06/2014; 86. DOI:10.1016/j.neuropharm.2014.05.043 · 5.11 Impact Factor
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    • "Both basic and clinical studies have shown that a dietary intake of n-3 PUFAs results in a reduction of pain associated with rheumatoid and inflammatory joint pain [4], [5], dysmenorrheal pain [6], fibromyalgia [7] and neuropathy [7]. On the other hand, there are several reports that resolvins D1 and E1, derived from docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), respectively, could effectively reduce inflammatory [8] and postoperative pain [9]. "
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    ABSTRACT: GPR40 has been reported to be activated by long-chain fatty acids, such as docosahexaenoic acid (DHA). However, reports studying functional role of GPR40 in the brain are lacking. The present study focused on the relationship between pain regulation and GPR40, investigating the functional roles of hypothalamic GPR40 during chronic pain caused using a complete Freund's adjuvant (CFA)-induced inflammatory chronic pain mouse model. GPR40 protein expression in the hypothalamus was transiently increased at day 7, but not at days 1, 3 and 14, after CFA injection. GPR40 was co-localized with NeuN, a neuron marker, but not with glial fibrillary acidic protein (GFAP), an astrocyte marker. At day 1 after CFA injection, GFAP protein expression was markedly increased in the hypothalamus. These increases were significantly inhibited by the intracerebroventricular injection of flavopiridol (15 nmol), a cyclin-dependent kinase inhibitor, depending on the decreases in both the increment of GPR40 protein expression and the induction of mechanical allodynia and thermal hyperalgesia at day 7 after CFA injection. Furthermore, the level of DHA in the hypothalamus tissue was significantly increased in a flavopiridol reversible manner at day 1, but not at day 7, after CFA injection. The intracerebroventricular injection of DHA (50 mu g) and GW9508 (1.0 mu g), a GPR40-selective agonist, significantly reduced mechanical allodynia and thermal hyperalgesia at day 7, but not at day 1, after CFA injection. These effects were inhibited by intracerebroventricular pretreatment with GW1100 (10 mg), a GPR40 antagonist. The protein expression of GPR40 was colocalized with that of beta-endorphin and proopiomelanocortin, and a single intracerebroventricular injection of GW9508 (1.0 mg) significantly increased the number of neurons double-stained for c-Fos and proopiomelanocortin in the arcuate nucleus of the hypothalamus. Our findings suggest that
    PLoS ONE 12/2013; 8(12):e81563. DOI:10.1371/journal.pone.0081563 · 3.23 Impact Factor
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