Spinal NK‐1 receptor‐expressing neurons and descending pathways support fentanyl‐induced pain hypersensitivity in a rat model of postoperative pain

Rivat, Cyril; Vera–Portocarrero, Louis P.; Ibrahim, Mohab; Mata, Heriberto P.; Stagg, Nicola J.; Felice, Milena De; Porreca, Frank; Malan, T. Philip

doi:10.1111/j.1460-9568.2009.06616.x

Cited by 58 publications

(66 citation statements)

References 65 publications

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“…Onset and duration of dynorphin up-regulation could be relevant to explain postoperative sensitization. The delayed increase in dynorphin observed in our study (days 4 -7) could explain the failure to reverse incisional pain after intrathecal administration of anti-dynorphin antiserum on the first day after surgery (Rivat et al, 2009). Moreover, intrathecal anti-dynorphin antiserum also failed to reduce pain hypersensitivity 2 days after sciatic nerve ligation in mice but was effective 10 days after surgery (Wang et al, 2001).…”

Section: Downloaded Frommentioning

confidence: 48%

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Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Campillo

González-Cuello²,

Cabañero³

et al. 2009

Mol Pharmacol

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In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the expression of c-Fos, prodynorphin (mRNA), and dynorphin in the spinal cord could participate in the molecular mechanisms underlying postoperative opioid-induced sensitization. In a mouse model of incisional pain, we evaluated thermal (Hargreaves test) and mechanical (von Frey) hyperalgesia during the first 21 postoperative days. Moreover, prodynorphin (mRNA, real-time polymerase chain reaction), dynorphin (enzymatic immunoassay), c-Fos expression, and ERK1/2 phosphorylation (both by immunohistochemistry) in the lumbar spinal cord were assessed. Surgery performed under remifentanil anesthesia induced a maximal decrease in nociceptive thresholds between 4 h and 2 days postoperatively (p Ͻ 0.001) that lasted 10 to 14 days compared with noninjured animals. In the same experimental conditions, a significant increase in prodynorphin mRNA expression (at 2 and 4 days) followed by a sustained increase of dynorphin (days 2 to 10) in the spinal cord was observed. We also identified an early expression of c-Fos immunoreactivity in the superficial laminae of the dorsal horn of the spinal cord (peak at 4 h; p Ͻ 0.001), together with a partial activation of ERK1/2 (4 h; p Ͻ 0.001). These findings suggest that activated ERK1/2 could induce c-Fos expression and trigger the transcription of prodynorphin in the spinal cord. This in turn would result in long-lasting increased levels of dynorphin that, in our model, could participate in the persistence of pain but not in the manifestation of first pain.In humans, exposure to -opioid receptor agonists during anesthesia induces delayed hyperalgesia, increasing pain and analgesic requirements in the postoperative period (Angst and Clark, 2006). The pronociceptive effects of opioids have also been reported in human volunteers and in animal models (Li et al., 2001;Angst et al., 2003). In a mouse model of postoperative pain, we have shown that postincisional pain is enhanced when the ultra-short-acting -opioid receptor agonist remifentanil is administered during anesthesia (Célé rier et al., 2006;Cabañ ero et al., 2009b). Remifentanil is commonly used in clinical practice to provide analgesia during surgery, although it has been associated with hyperalgesia in the immediate postoperative period (Angst and Clark, 2006;Joly et al., 2005).The mechanisms and signal transduction pathways that mediate pain sensitization after opioid administration are not well known. Multiple central and peripheral pathways and mechanisms have been implicated, including C-fiber sensitization, protein kinase C, the nitric oxide system, N-methyl-D-aspartate (NMDA) receptors, mitogen-activated protein kinases (MAPKs) and spinal dynorphin, among others (Angst and Clark, 2006). It has also been shown that down-regulation of ␦-opioid receptor mRNA in the dorsal root ganglia contributes to remifentanil and surgery-i...

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Section: Downloaded Frommentioning

confidence: 48%

“…In a model of postoperative pain in rats, Rivat et al (2009) found a significant increase in spinal dynorphin 1 day after fentanyl administration or surgical incision, with a greater increase when both procedures were combined. In the present report, we were able to confirm and expand these results in mice, but using remifentanil.…”

Section: Discussionmentioning

confidence: 95%

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Campillo

González-Cuello²,

Cabañero³

et al. 2009

Mol Pharmacol

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“…These data suggest that different molecular adaptations may underlie the maintenance of tactile and thermal hypersensitivities in chronic pain. Ablation of NK 1 -expressing neurons in rats using saporin-conjugated SP blocked opioid hypersensitivity/tolerance in naïve and injured rats (Vera-Portocarrero et al, 2007;Rivat et al, 2009). Results with TY027 may reflect accumulation of peptide in lipid membranes known to alter the bioactivity (Yamamoto et al, 2009).…”

Section: Discussionmentioning

confidence: 98%

“…The SP-NK 1 system is implicated in the mechanisms underlying opioid antinociceptive tolerance, withdrawal, and reward (Commons, 2010). Chemical ablation of NK 1 -expressing neurons in rodents attenuated hyperalgesia (Mantyh et al, 1997;Vera-Portocarrero et al, 2007;Rivat et al, 2009), reward/anxiety (Gadd et al, 2003), and reduced symptoms of physical withdrawal (Maldonado et al, 1993). Coadministration of morphine with an NK 1 antagonist attenuated the development of opioid antinociceptive tolerance in rats (Powell et al, 2003), with NK 1 antagonists acting as antiemetics (Munoz and Covenas, 2010).…”

Section: Introductionmentioning

confidence: 99%

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

Largent-Milnes

Brookshire

Skinner

et al. 2013

J Pharmacol Exp Ther

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The most highly abused prescription drugs are opioids used for the treatment of pain. Physician-reported drug-seeking behavior has resulted in a significant health concern among doctors trying to adequately treat pain while limiting the misuse or diversion of pain medications. In addition to abuse liability, opioid use is associated with unwanted side effects that complicate pain management, including opioid-induced emesis and constipation. This has resulted in restricting long-term doses of opioids and inadequate treatment of both acute and chronic debilitating pain, demonstrating a compelling need for novel analgesics. Recent reports indicate that adaptations in endogenous substance P/neurokinin-1 receptor (NK 1 ) are induced by chronic pain and sustained opioid exposure, and these changes may contribute to processes responsible for opioid abuse liability, emesis, and analgesic tolerance. Here, we describe a multifunctional mu-/delta-opioid agonist/NK 1 antagonist compound [Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-Bn(CF 3 ) 2 (TY027)] that has a preclinical profile of excellent antinociceptive efficacy, low abuse liability, and no opioid-related emesis or constipation. In rodent models of acute and neuropathic pain, TY027 demonstrates analgesic efficacy following central or systemic administration with a plasma half-life of more than 4 hours and central nervous system penetration. These data demonstrate that an innovative opioid designed to contest the pathology created by chronic pain and sustained opioids results in antinociceptive efficacy in rodent models, with significantly fewer side effects than morphine. Such rationally designed, multitargeted compounds are a promising therapeutic approach in treating patients who suffer from acute and chronic pain.

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“…These observations indicate that the TRPV1 and SP-NK1R axis acts as a defense against damage from sepsis. SP-and NK1R-containing PANs were shown to be involved to some extent in hypersensitivity to surgical pain in rats (26). PANs in the rat spinal cord co-express μ-and δ-opioid receptors, and agonists of both opioid receptors potently inhibited capsaicin-induced SP release (27).…”

Section: Roles Of Tks In Nociceptionmentioning

confidence: 99%

Tachykinin: recent developments and novel roles in health and disease

Onaga

2014

Biomolecular Concepts

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Over 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP, neurokinin A (NKA), and neurokinin B (NKB) are representative peptides in mammalian species. SP and NKA are major excitatory neurotransmitters in the peripheral nervous system, while NKB is primarily involved in the central nervous system (CNS). Moreover, TK peptides play roles not only as neurotransmitters but also as local factors and are involved in almost all aspects of the regulation of physiological functions and pathophysiological processes. The role of SP as a mediator of pain processing and inflammation in peripheral tissues in coordination with transient receptor potential channels is well established, while novel aspects of TKs in relation to hematopoiesis, venous thromboembolism, tendinopathy, and taste perception have been clarified. In the CNS, the NKB signaling system in the hypothalamus has been shown to play a crucial role in the regulation of gonadotropin hormone secretion and the onset of puberty, and molecular biological studies have elucidated novel prophylaxic activities of TKs against neurogenic movement disorders based on their molecular structure. This review provides an overview of the novel aspects of TKs reported around the world in the last 5 years, with particular focus on nociception, inflammation, hemopoiesis, gonadotropin secretion, and CNS diseases.

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Spinal NK‐1 receptor‐expressing neurons and descending pathways support fentanyl‐induced pain hypersensitivity in a rat model of postoperative pain

Cited by 58 publications

References 65 publications

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Increased Spinal Dynorphin Levels and Phospho-Extracellular Signal-Regulated Kinases 1 and 2 and c-Fos Immunoreactivity after Surgery under Remifentanil Anesthesia in Mice

Building a Better Analgesic: Multifunctional Compounds that Address Injury-Induced Pathology to Enhance Analgesic Efficacy while Eliminating Unwanted Side Effects

Tachykinin: recent developments and novel roles in health and disease

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