TY - JOUR
T1 - Morphine-induced early delays in wound closure
T2 - Involvement of sensory neuropeptides and modification of neurokinin receptor expression
AU - Rook, Jerri M.
AU - Hasan, Wohaib
AU - McCarson, Kenneth E.
N1 - Funding Information:
This study was supported in part by DA12505 (KMcC) and a Basic Science Research Pilot Grant from the Lied foundation/KUMC Research Institute (KMcC) and an award from the KUMC Biomedical Research Training Program (JR). The authors would like to thank Michelle Winter and Donald Warn, Ph.D. for their expert technical assistance and the contributions of the KUMC IDDRC (NICHD HD 02528) core facilities.
PY - 2009/6/1
Y1 - 2009/6/1
N2 - 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 mM 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.
AB - 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 mM 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.
KW - Macrophage
KW - Myofibroblast
KW - Neurokinin A
KW - Primary afferent neuron
KW - Skin
KW - Substance P
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U2 - 10.1016/j.bcp.2009.03.003
DO - 10.1016/j.bcp.2009.03.003
M3 - Article
C2 - 19428329
AN - SCOPUS:64249140130
SN - 0006-2952
VL - 77
SP - 1747
EP - 1755
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 11
ER -