Prevention of Chronic Post-Thoracotomy Pain in Rats By Intrathecal Resolvin D1 and D2: Effectiveness of Perioperative and Delayed Drug Delivery

Abstract

Thoracotomy results in a high frequency of chronic post-operative pain. Resolvins are endogenous molecules, synthesized and released by activated immune cells, effective against inflammatory and neuropathic pain. Different resolvins have differential actions on selective neuronal and glial receptors and enzymes. This paper examines the ability of intrathecal Resolvin D1 (RvD1) and Resolvin D2 (RvD2) to reduce chronic postthoracotomy pain in rats. Thoracotomy, involving intercostal incision and rib retraction, resulted in a decrease in the mechanical force threshold to induce nocifensive behavior, an enlargement of the pain-sensitive area, and an increase in the fraction of rats showing nocifensive behavior, all for at least 5 weeks. The qualitative nature of the behavioral responses to tactile stimulation changed dramatically after thoracotomy, including the appearance of vigorous behaviors, such as turning, shuddering, and squealing, all absent in naive rats. Intrathecal delivery of RvD1 (30ng/30µL), at surgery or 4 days later, halved the spread of the mechano-sensitive area, lowered by 60% the percent of rats with tactile hypersensitivity, and reduced the drop in threshold for a nocifensive response, along with a reduction in the occurrence of vigorous nocifensive responses. RvD2’s actions on threshold changes were statistically the same. These findings suggest that intrathecal resolvins, delivered pre-operatively or several days later, can prevent chronic post-operative hyperalgesia.

Distinct Analgesic Actions of DHA and DHA-Derived Specialized Pro-Resolving Mediators on Post-operative Pain After Bone Fracture in Mice

“…However, IT post-treatment of NPD1 was as effective as gabapentin in attenuating nerve injury-induced late-phase mechanical allodynia, despite a striking dose difference (500 ng NPD1 vs. 100 μg gabapentin; Xu et al, 2013b ). Despite the effectiveness of the post-operative treatment, we also have to point out that SPMs are more effective in preventing the development of chronic POP and neuropathic pain ( Huang et al, 2011 ; Xu et al, 2013b ; Wang and Strichartz, 2017 ).…”

“…SPMs, such as resolvins, lipoxins, neuroprotectins, and maresins, are derived from omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) and exhibit potent anti-inflammatory and pro-resolution actions in various animal models of inflammation ( Serhan et al, 2008 ; Norling et al, 2016 ). Many groups have demonstrated that peripheral, spinal, or systemic administration of lipoxins (LXA 4 ), resolvins such as RvD1, D2, and E1 (RvD1, RvD2, and RvE1), NPD1, and MaR1 at very low doses (nanogram range), effectively reduced inflammatory pain ( Svensson et al, 2007 ; Bang et al, 2010 ; Xu et al, 2010 ; Lima-Garcia et al, 2011 ; Park et al, 2011a , b ; Sommer and Birklein, 2011 ; Terrando et al, 2013 ), POP after thoracotomy and muscle retraction ( Huang et al, 2011 ; Wang and Strichartz, 2017 ), as well as neuropathic pain after nerve injury ( Xu et al, 2013a , b ) and spinal cord injury ( Martini et al, 2016 ).…”

Resolvin D5 Inhibits Neuropathic and Inflammatory Pain in Male But Not Female Mice: Distinct Actions of D-Series Resolvins in Chemotherapy-Induced Peripheral Neuropathy

“…SPMs have been shown to produce pain relief in inflammatory pain (Svensson et al, 2007; Bang et al, 2010a; Xu et al, 2010; Lima-Garcia et al, 2011; Park et al, 2011b), postoperative pain (Huang et al, 2011; Wang and Strichartz, 2017; Zhang et al, 2018), and nerve trauma-induced neuropathic pain (Xu et al, 2013a; Xu et al, 2013b). CIPN is a unique type of neuropathic pain, as there is very limited activation of microglia in the spinal cord after CIPN by PTX (Zheng et al, 2011; Robinson et al, 2014).…”

“…Studies from different laboratories have also demonstrated potent analgesic actions of resolvins (e.g., RvE1, RvD1, and RvD2) in animal models of inflammatory pain (Bang et al, 2010a; Xu et al, 2010; Lima-Garcia et al, 2011; Park et al, 2011b), postoperative pain (Huang et al, 2011; Wang and Strichartz, 2017; Zhang et al, 2018), and nerve trauma-induced neuropathic pain (Xu et al, 2013b). Mechanistically, RvE1, RvD1, and RvD2 suppressed the processing of nociceptive information in the spinal cord pain circuit (Xu et al, 2010; Park et al, 2011b; Meesawatsom et al, 2016).…”

Peripheral Interaction of Resolvin D1 and E1 with Opioid Receptor Antagonists for Antinociception in Inflammatory Pain in Rats

“…For example, intrathecal application of RvD1 and RvE1 increases thermal nociceptive thresholds after CFA (Xu et al, 2010 ). Spinal RvD1 elicits potent antinociceptive effect in lumbar disc herniation (Liu et al, 2016 ), prevents long-term hypersensitivity after thoracotomy (Wang and Strichartz, 2017 ) as well as chronic pancreatitis-induced visceral pain (Quan-Xin et al, 2012 ) and 17(R)-HDoHE reverses pain behavior in two models of osteoarthritis pain (Huang et al, 2017 ). Less is known about peripheral effects and about mechanical hypersensitivity: intraplantar RvD1 and RvE1 reduced carrageen-induced thermal hypersensitivity and pain behavior evoked by capsaicin or AITC, respectively (Park et al, 2011b ).…”