Limits...
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

Heat pain thresholds and secondary hyperalgesia areas before and after a mild heat injury.Heat pain thresholds (white circles; left y-axis) and secondary hyperalgesia areas (red circles; right y-axis) before and, 60, 120 and 180 min, after a mild heat injury (MHI). Values represent mean of Day 1 and Day 3 values (mean ± 95% CI). * P < 0.01; ** P < 0.005; **** P < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4549112&req=5

pone.0134441.g004: Heat pain thresholds and secondary hyperalgesia areas before and after a mild heat injury.Heat pain thresholds (white circles; left y-axis) and secondary hyperalgesia areas (red circles; right y-axis) before and, 60, 120 and 180 min, after a mild heat injury (MHI). Values represent mean of Day 1 and Day 3 values (mean ± 95% CI). * P < 0.01; ** P < 0.005; **** P < 0.0005.

Mentions: Changes induced by MHI Day 1/Day 3: pain intensity was 32 (24–39) visual analogue scale units (VAS; 0–100) with no difference between Day 1 and Day 3. MHI produced a robust and short-lasting primary and secondary hyperalgesia as reflected by the development of heat (F(3,24) = 26.1, P < 0.00001) and mechanical hypersensitivity (F(3,33) = 13.5, P < 0.00001, Fig 4; S2 Table).


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)

Heat pain thresholds and secondary hyperalgesia areas before and after a mild heat injury.Heat pain thresholds (white circles; left y-axis) and secondary hyperalgesia areas (red circles; right y-axis) before and, 60, 120 and 180 min, after a mild heat injury (MHI). Values represent mean of Day 1 and Day 3 values (mean ± 95% CI). * P < 0.01; ** P < 0.005; **** P < 0.0005.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134441.g004: Heat pain thresholds and secondary hyperalgesia areas before and after a mild heat injury.Heat pain thresholds (white circles; left y-axis) and secondary hyperalgesia areas (red circles; right y-axis) before and, 60, 120 and 180 min, after a mild heat injury (MHI). Values represent mean of Day 1 and Day 3 values (mean ± 95% CI). * P < 0.01; ** P < 0.005; **** P < 0.0005.
Mentions: Changes induced by MHI Day 1/Day 3: pain intensity was 32 (24–39) visual analogue scale units (VAS; 0–100) with no difference between Day 1 and Day 3. MHI produced a robust and short-lasting primary and secondary hyperalgesia as reflected by the development of heat (F(3,24) = 26.1, P < 0.00001) and mechanical hypersensitivity (F(3,33) = 13.5, P < 0.00001, Fig 4; S2 Table).

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