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Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human.

Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU - PLoS ONE (2015)

Bottom Line: Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg).Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.EudraCT 2012-005663-27.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark.

ABSTRACT

Unlabelled: Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.

Trial registration: EudraCT 2012-005663-27.

No MeSH data available.


Related in: MedlinePlus

Individual trajectories of secondary hyperalgesia areas during the early and late phase after a mild heat injury.Individual trajectories of secondary hyperalgesia areas (n = 12) during the early phase (0–3 hrs) and the late phase (165–169 hrs) after induction of the mild heat injury (MHI). Data are from naloxone (A) and placebo (B) sessions. The trajectories of the four naloxone responders, indicating presence of endogenous opioid masked sensitization, are delineated by red circles and the trajectories from the eight non-responders by blue filled circles. MHI and drug administration are indicated by vertical arrows. One (#11) of the responders demonstrated residual SHA at 165 hrs after the induction of MHI (indicated by oblique arrow; B), but not during placebo. Secondary hyperalgesia areas developed in 4/12 subjects (#2,6,7,11) after naloxone (A) and in 0/12 after placebo (B).
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pone.0134441.g005: Individual trajectories of secondary hyperalgesia areas during the early and late phase after a mild heat injury.Individual trajectories of secondary hyperalgesia areas (n = 12) during the early phase (0–3 hrs) and the late phase (165–169 hrs) after induction of the mild heat injury (MHI). Data are from naloxone (A) and placebo (B) sessions. The trajectories of the four naloxone responders, indicating presence of endogenous opioid masked sensitization, are delineated by red circles and the trajectories from the eight non-responders by blue filled circles. MHI and drug administration are indicated by vertical arrows. One (#11) of the responders demonstrated residual SHA at 165 hrs after the induction of MHI (indicated by oblique arrow; B), but not during placebo. Secondary hyperalgesia areas developed in 4/12 subjects (#2,6,7,11) after naloxone (A) and in 0/12 after placebo (B).

Mentions: MHI-related changes in SHA induced by naloxone Day 3/Day 4: after recovery of hyperalgesia indices at 168 hrs after MHI, the naloxone infusion produced large secondary hyperalgesia areas (SHA) in 4/12 subjects (median [25–75% IQR]: 90.3 cm2 [63.2–145.3 cm2]; #2,6,7,11; Fig 5A), while the placebo infusion did not produce SHA in any subject (0 cm2 [0–1 cm2]; Fig 5B; S2 Table). Two subjects on the saline day and one subject on the naloxone day had residual secondary hyperalgesia areas (SHA) 165 hrs post-MHI: #9 (1.4 cm2) and #11 (28.9 cm2), and, #7 (2.6 cm2), respectively.


Endogenous Opioid-Masked Latent Pain Sensitization: Studies from Mouse to Human.

Pereira MP, Donahue RR, Dahl JB, Werner M, Taylor BK, Werner MU - PLoS ONE (2015)

Individual trajectories of secondary hyperalgesia areas during the early and late phase after a mild heat injury.Individual trajectories of secondary hyperalgesia areas (n = 12) during the early phase (0–3 hrs) and the late phase (165–169 hrs) after induction of the mild heat injury (MHI). Data are from naloxone (A) and placebo (B) sessions. The trajectories of the four naloxone responders, indicating presence of endogenous opioid masked sensitization, are delineated by red circles and the trajectories from the eight non-responders by blue filled circles. MHI and drug administration are indicated by vertical arrows. One (#11) of the responders demonstrated residual SHA at 165 hrs after the induction of MHI (indicated by oblique arrow; B), but not during placebo. Secondary hyperalgesia areas developed in 4/12 subjects (#2,6,7,11) after naloxone (A) and in 0/12 after placebo (B).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4549112&req=5

pone.0134441.g005: Individual trajectories of secondary hyperalgesia areas during the early and late phase after a mild heat injury.Individual trajectories of secondary hyperalgesia areas (n = 12) during the early phase (0–3 hrs) and the late phase (165–169 hrs) after induction of the mild heat injury (MHI). Data are from naloxone (A) and placebo (B) sessions. The trajectories of the four naloxone responders, indicating presence of endogenous opioid masked sensitization, are delineated by red circles and the trajectories from the eight non-responders by blue filled circles. MHI and drug administration are indicated by vertical arrows. One (#11) of the responders demonstrated residual SHA at 165 hrs after the induction of MHI (indicated by oblique arrow; B), but not during placebo. Secondary hyperalgesia areas developed in 4/12 subjects (#2,6,7,11) after naloxone (A) and in 0/12 after placebo (B).
Mentions: MHI-related changes in SHA induced by naloxone Day 3/Day 4: after recovery of hyperalgesia indices at 168 hrs after MHI, the naloxone infusion produced large secondary hyperalgesia areas (SHA) in 4/12 subjects (median [25–75% IQR]: 90.3 cm2 [63.2–145.3 cm2]; #2,6,7,11; Fig 5A), while the placebo infusion did not produce SHA in any subject (0 cm2 [0–1 cm2]; Fig 5B; S2 Table). Two subjects on the saline day and one subject on the naloxone day had residual secondary hyperalgesia areas (SHA) 165 hrs post-MHI: #9 (1.4 cm2) and #11 (28.9 cm2), and, #7 (2.6 cm2), respectively.

Bottom Line: Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg).Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.EudraCT 2012-005663-27.

View Article: PubMed Central - PubMed

Affiliation: Department of Anaesthesia, Centre of Head and Orthopaedics, Rigshospitalet, Copenhagen, Denmark.

ABSTRACT

Unlabelled: Following the resolution of a severe inflammatory injury in rodents, administration of mu-opioid receptor inverse agonists leads to reinstatement of pain hypersensitivity. The mechanisms underlying this form of latent pain sensitization (LS) likely contribute to the development of chronic pain, but LS has not yet been demonstrated in humans. Using a C57BL/6 mouse model of cutaneous mild heat injury (MHI) we demonstrated a dose-dependent reinstatement of pain sensitization, assessed as primary (P < 0.001) and secondary hyperalgesia (P < 0.001) by naloxone (0.3–10 mg/kg), 168 hrs after the induction of MHI. Forward-translating the dose data to a human MHI model (n = 12) we could show that LS does indeed occur after naloxone 2 mg/kg, 168 hrs after a MHI. Our previous unsuccessful efforts to demonstrate unmasking of LS in humans are thus likely explained by an insufficient naloxone dose (0.021 mg/kg). However, while LS was consistently demonstrated in 21/24 mice, LS was only seen in 4/12 subjects. This difference is likely due to selection bias since the C57BL/6 mouse strain exhibits markedly enhanced pain sensitivity in assays of acute thermal nociception. Future exploratory studies in humans should prioritize inclusion of “high-sensitizers” prone to develop LS and use post-surgical models to elucidate markers of vulnerability to chronic postsurgical pain.

Trial registration: EudraCT 2012-005663-27.

No MeSH data available.


Related in: MedlinePlus