Modulation of peripheral inflammation by locally administered endomorphin-1

Khalil, Zeinab; Sanderson, Katarina; Modig, M.; Nyberg, Frida

doi:10.1007/s000110050502

Cited by 29 publications

(14 citation statements)

References 32 publications

(58 reference statements)

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“…40 Opioids may inhibit the release as well as function of SP, because MOPr- and DOPr-agonists perfused with SP reduced plasma extravasation and blood flow, in an OPr-dependent manner. 41,42 Thus, sustained increase in neuropeptides in the skin of MOPr-KO mice during the maturation phase may interfere with healing by promoting neurogenic inflammation. Taken together these observations suggest that morphine treatment reduces neuroinflammation in the wounds, which may contribute to morphine-induced healing.…”

Section: Discussionmentioning

confidence: 99%

Opioids and opioid receptors orchestrate wound repair

Wang

Gupta

Poonawala

et al. 2017

Translational Research

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We have previously shown that topical opioids including morphine and its congeners promote healing of full thickness ischemic wounds in rats. We examined the contribution of mu opioid receptor (MOPr)-mediated healing of full thickness ischemic wounds using MOPr and delta or kappa opioid receptor (DOPr or KOPr) knockout (KO) mice. Wound closure in the early (day 5) as well as later phases was delayed in topical morphine or PBS treated MOPr-KO mice compared to reciprocal treatments of wounds in wild-type (WT) mice. MOPr expression was significantly upregulated at 30 min in the wound margins and colocalized with wound margins and vasculature in the epidermal and dermal layers of the skin. We next examined whether neuropeptide expression was involved in the mechanism of MOPr-mediated wound closure. Substance P (SP) and calcitonin gene related peptide (CGRP) immunoreactivity (ir) was significantly increased in the skin of MOPr-KO mice as compared to WT mice. Neuropeptide-ir was increased significantly in PBS-treated wounds of MOPr and WT mice, but morphine treatment reduced neuropeptide immunoreactivity in both as compared to PBS. Wounding of keratinocytes led to the release of opioid peptide beta-endorphin (β-END) in conditioned medium, which stimulated the proliferation of endothelial cells. MOPr-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2, CTOP) and non-selective OPr antagonist naloxone inhibited endothelial proliferation induced by wounded keratinocyte conditioned medium. Additionally, accelerated wound area closure in vitro by morphine was suppressed by methylnaltrexone, a non-selective OPr antagonist with high affinity for MOPr. Morphine and its congeners stimulated the proliferation of endothelial cells from WT mice but not those from MOPr-KO mice. Furthermore, morphine-induced mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) phosphorylation in endothelial cells was significantly decreased in MOPr-KO mice as compared to WT mice. Collectively, these data suggest that MOPr plays a critical role in the proliferation phase with the formation of granulation tissue during wound healing.

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Section: Discussionmentioning

confidence: 99%

Opioids and opioid receptors orchestrate wound repair

Wang

Gupta

Poonawala

et al. 2017

Translational Research

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“…Furthermore, opioids can reduce proinflammatory cytokines and adhesion molecules (Belkowski et al, 1995;Wilson et al, 1998;Walker et al, 2000;Philippe et al, 2003), edema and plasma extravasation (Jin et al, 1999;Khalil et al, 1999;Romero et al, 2005;Jiménez et al, 2006;Börzsei et al, 2008), and radiological and histological parameters (Binder et al, 2000(Binder et al, , 2001Walker, 2003). In human tissue sample, opioids have been shown to reduce proinflammatory cytokines, matrix metalloproteinase, and synovial leukocyte counts (Raap et al, 2000;Takeba et al, 2001;Straub et al, 2008).…”

Section: Opioid Effects On Inflammation and Wound Healingmentioning

confidence: 99%

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

2011

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“…Opioid receptor agonists exhibit anti-inflammatory effects [11, 12]. Activation of opioid receptors on primary afferent neurons reduces the excitability of these neurons suppressing the antidromic release of pro-inflammatory neuropeptides such as substance P (SP) and neurokinin-A (NKA) [1, 13, 14].…”

Section: Introductionmentioning

confidence: 99%

Morphine-induced early delays in wound closure: Involvement of sensory neuropeptides and modification of neurokinin receptor expression

Rook

Hasan

McCarson

2009

Biochemical Pharmacology

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Dose-limiting side effects of centrally-acting opioid drugs have led to the use of topical opioids to reduce the pain associated with chronic cutaneous wounds. However, previous studies indicate that topical morphine application impairs wound healing. This study was designed to elucidate the mechanisms by which morphine delays wound closure. Rats were depleted of sensory neuropeptides by treatment with capsaicin, and full-thickness 4 mm diameter wounds were excised from the intrascapular region. Wounds were treated topically twice daily with 5 mM morphine sulfate, 1 mM substance P, 1 mM neurokinin A, or 5 mM morphine combined with 1 m M substance P or neurokinin A and wound areas assessed. During closure, wound tissue was taken 1, 3, 5, and 8 days post-wounding from control and morphine-treated rats and immunostained for neurokinin receptors and markers for macrophages, myofibroblasts, and vasculature. Results obtained from capsaicin-treated animals demonstrated a significant delay in the early stages of wound contraction that was reversed by neuropeptide application. Treatment of capsaicin-treated rats with topical morphine did not further delay wound closure, suggesting that topical opioids impair wound closure via the inhibition of peripheral neuropeptide release into the healing wound. Morphine application altered neurokinin-1 and neurokinin-2 receptor expression in inflammatory and parenchymal cells essential for wound healing in a cell-specific manner, demonstrating a direct effect of morphine on neurokinin receptor regulation within an array of cells involved in wound healing. These data provide evidence indicating a potentially detrimental effect of topical morphine application on the dynamic wound healing process.

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Modulation of peripheral inflammation by locally administered endomorphin-1

Cited by 29 publications

References 32 publications

Opioids and opioid receptors orchestrate wound repair

Opioids and opioid receptors orchestrate wound repair

Modulation of Peripheral Sensory Neurons by the Immune System: Implications for Pain Therapy

Morphine-induced early delays in wound closure: Involvement of sensory neuropeptides and modification of neurokinin receptor expression

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