Evidence for Separate Involvement of Different μ-Opioid Receptor Subtypes in Itch and Analgesia Induced by Supraspinal Action of Opioids

Andoh, Tsugunobu; Yageta, Yuichi; Konno, Mitsuhiro; Yamaguchi-Miyamoto, Tomomi; Takahata, Hiroki; Nishimura, Hiroshi; Nemoto, Hideo; Kuraishi, Yasushi

doi:10.1254/jphs.08004sc

Cited by 23 publications

(17 citation statements)

References 16 publications

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“…Our results are also in line with Andoh et al (2008) who examined the involvement of the 5-LO pathway in the itch induced by SP. An intradermal injection of SP produced a strong increase in the cutaneous content of LTB 4 , and this action was practically abolished by dexamethasone.…”

Section: Discussionsupporting

confidence: 91%

Substance P Upregulates LTB4 in Rat Adherent Macrophages from Granuloma Induced by KMnO4

et al. 2009

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Substance P (SP) is an important neuropeptide involved in neurogenic inflammation and most of its pathophysiological functions are mediated through binding to the neurokinin-1 receptor. SP exerts various proinflammatory actions on immune-cells, including macrophages. Several compounds such as cytokines have the capacity to activate and stimulate macrophages to produce arachidonic acid oxygenation and lipoxygenation products. Leukotriene B4 (LTB4) is one of the most important mediators of leukocyte activation in acute and chronic inflammatory reactions. LTB4 stimulates chemotaxis, lysosomal enzyme release, and cell aggregation. In this report, we studied the effect of SP on rat adherent granuloma macrophages (RAGMs). The chronic granuloma in rat was induced by dorsal injections of a potassium permanganate (KMnO4) saturated crystal solution (200 microl of a 1:40 dilution). After 7 days, all rats developed a subcutaneous granuloma in the injection site from which infiltrated macrophages were extracted, isolated, and cultured in vitro. We tested the hypothesis that SP stimulates the production of LTB4 in RAGMs and increases lipoxygenase expression. Here we show that the cell-free supernatant of RAGMs stimulated with SP (10 microM), resulted in statistically significant increases of LTB4 Preincubation of RAGMs with NDGA (nordihydroguaiaretic acid (10 microM), completely abolished the production of LTB(4) in the supernatants and lipoxygenase expression on RAGMs challenged with SP, or the cation ionophore A23187 (positive control). Similar effects were obtained when the cells were pretreated with dexamethasone (10 microM). Our results suggest that SP is able to stimulate the release of LTB4 and lipoxygenase expression in macrophages from chronic inflammatory granuloma and provide further evidence for a neuroinflammatory pathway.

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Section: Discussionsupporting

confidence: 91%

Substance P Upregulates LTB4 in Rat Adherent Macrophages from Granuloma Induced by KMnO4

et al. 2009

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“…For example, MOR1 consists of exon 1~4, while MOR1D of exons 1~3 and 8~9 (Figure 2C). The multiplicity of the Oprm isoform system has been suggested to underlie the heterogeneity and variability of analgesic and scratching effects exerted by different agonists (Andoh et al, 2008; Pasternak, 2004; Ravindranathan et al, 2009). We postulated that different isoforms are responsible for MIS and MIA respectively.…”

Section: Resultsmentioning

confidence: 99%

Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids

Liu

Sun

et al. 2011

Cell

251

258

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SUMMARY Why do opiates make human beings itch ? Spinal opioid-induced itch, a prevalent side effect of pain management, has been considered to occur as a result of pain inhibition. We report that morphine-induced scratching (MIS) is abolished in mice lacking either gastrin-releasing peptide receptor (GRPR) or the μ opioid receptor (MOR). Using exon-specific knockdown, we identified the MOR1D isoform as essential for MIS, whereas MOR1 is important for morphine-induced analgesia (MIA) with no cross activity present. MOR1D and GRPR form constitutive heterodimers in the spinal cord and relay itch information upon morphine activation. Morphine induces internalization of both GRPR and MOR1D, whereas GRP induces that of GRPR but not MOR1D, when co-expressed. Moreover, GRP-induced scratching (GIS) is independent of MOR activation. These results suggest a unidirectional cross-activation of GRPR signaling by MOR1D via heterodimerization, and that opioid-induced itch is an active process concomitant with but independent of opioid analgesia.

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“…Although many had assumed that that this was attributed to histamine release mediated through the same mu receptors as analgesia, several reports suggest that this may not entirely explain the symptom. According to Andoh et al (2008), intracisternal morphine and morphine-6b-glucuronide are both analgesic, but only morphine produces pruritus. Furthermore, the facial scratching seen with morphine is insensitive to naloxonazine while analgesia is blocked, leading them to conclude that morphine analgesia and pruritus are mediated through different receptor subtypes.…”

Section: E Other Actionsmentioning

confidence: 99%

Mu Opioids and Their Receptors: Evolution of a Concept

2013

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Evidence for Separate Involvement of Different μ-Opioid Receptor Subtypes in Itch and Analgesia Induced by Supraspinal Action of Opioids

Cited by 23 publications

References 16 publications

Substance P Upregulates LTB4 in Rat Adherent Macrophages from Granuloma Induced by KMnO4

Substance P Upregulates LTB4 in Rat Adherent Macrophages from Granuloma Induced by KMnO4

Unidirectional Cross-Activation of GRPR by MOR1D Uncouples Itch and Analgesia Induced by Opioids

Mu Opioids and Their Receptors: Evolution of a Concept

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