TY - JOUR
T1 - Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn
AU - Custodio-Patsey, Lilian
AU - Donahue, Renée R.
AU - Fu, Weisi
AU - Lambert, Joshua
AU - Smith, Bret N.
AU - Taylor, Bradley K.
N1 - Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/2
Y1 - 2020/2
N2 - Tissue injury produces a delicate balance between latent pain sensitization (LS) and compensatory endogenous opioid receptor analgesia that continues for months, even after re-establishment of normal pain thresholds. To evaluate the contribution of mu (MOR), delta (DOR), and/or kappa (KOR) opioid receptors to the silencing of chronic postoperative pain, we performed plantar incision at the hindpaw, waited 21 days for the resolution of hyperalgesia, and then intrathecally injected subtype-selective ligands. We found that the MOR-selective inhibitor CTOP (1–1000 ng) dose-dependently reinstated mechanical hyperalgesia. Two DOR-selective inhibitors naltrindole (1–10 μg) and TIPP[Ψ] (1–20 μg) reinstated mechanical hyperalgesia, but only at the highest dose that also produced itching, licking, and tail biting. Both the prototypical KOR-selective inhibitors nor-BNI (0.1–10 μg) and the newer KOR inhibitor with more canonical pharmocodynamic effects, LY2456302 (0.1–10 μg), reinstated mechanical hyperalgesia. Furthermore, LY2456302 (10 μg) increased the expression of phosphorylated signal-regulated kinase (pERK), a marker of central sensitization, in dorsal horn neurons but not glia. Sex studies revealed that LY2456302 (0.3 μg) reinstated hyperalgesia and pERK expression to a greater degree in female as compared to male mice. Our results suggest that spinal MOR and KOR, but not DOR, maintain LS within a state of remission to reduce the intensity and duration of postoperative pain, and that endogenous KOR but not MOR analgesia is greater in female mice.
AB - Tissue injury produces a delicate balance between latent pain sensitization (LS) and compensatory endogenous opioid receptor analgesia that continues for months, even after re-establishment of normal pain thresholds. To evaluate the contribution of mu (MOR), delta (DOR), and/or kappa (KOR) opioid receptors to the silencing of chronic postoperative pain, we performed plantar incision at the hindpaw, waited 21 days for the resolution of hyperalgesia, and then intrathecally injected subtype-selective ligands. We found that the MOR-selective inhibitor CTOP (1–1000 ng) dose-dependently reinstated mechanical hyperalgesia. Two DOR-selective inhibitors naltrindole (1–10 μg) and TIPP[Ψ] (1–20 μg) reinstated mechanical hyperalgesia, but only at the highest dose that also produced itching, licking, and tail biting. Both the prototypical KOR-selective inhibitors nor-BNI (0.1–10 μg) and the newer KOR inhibitor with more canonical pharmocodynamic effects, LY2456302 (0.1–10 μg), reinstated mechanical hyperalgesia. Furthermore, LY2456302 (10 μg) increased the expression of phosphorylated signal-regulated kinase (pERK), a marker of central sensitization, in dorsal horn neurons but not glia. Sex studies revealed that LY2456302 (0.3 μg) reinstated hyperalgesia and pERK expression to a greater degree in female as compared to male mice. Our results suggest that spinal MOR and KOR, but not DOR, maintain LS within a state of remission to reduce the intensity and duration of postoperative pain, and that endogenous KOR but not MOR analgesia is greater in female mice.
KW - Dorsal horn
KW - Hyperalgesia
KW - Kappa opioid receptor
KW - Mu opioid receptor
KW - Pain
KW - Postoperative
KW - Sex
KW - Spinal cord
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U2 - 10.1016/j.neuropharm.2019.107726
DO - 10.1016/j.neuropharm.2019.107726
M3 - Article
C2 - 31351975
AN - SCOPUS:85075740318
SN - 0028-3908
VL - 163
JO - Neuropharmacology
JF - Neuropharmacology
M1 - 107726
ER -