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Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision.

Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD - Mol Pain (2008)

Bottom Line: Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect.Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. liang@anesiva.com

ABSTRACT

Background: The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored.

Results: In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.

Conclusion: The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.

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Related in: MedlinePlus

Mechanical nociceptive thresholds after drug pretreatment and hindpaw incision. Panel A displays the mechanical thresholds of mice in four different treatment groups: saline pretreatment/no incision, saline pretreatment/incision, morphine pretreatment/no incision, morphine pretreatment/incision. The values labeled pre-incision represent the nociceptive thresholds measured after 4 days of saline or morphine treatment but prior to hind paw incision. In panel B data are presented representing mechanical nociceptive thresholds in mice undergoing saline or morphine treatment beginning at the time of incision. Nociceptive thresholds were measured immediately before that day's dose of morphine. The statistical analysis presented reflects the results of two-way ANOVA comparing saline/incision values to morphine/incision ones. *p < 0.05, **p < 0.01, N = 6/group.
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Figure 1: Mechanical nociceptive thresholds after drug pretreatment and hindpaw incision. Panel A displays the mechanical thresholds of mice in four different treatment groups: saline pretreatment/no incision, saline pretreatment/incision, morphine pretreatment/no incision, morphine pretreatment/incision. The values labeled pre-incision represent the nociceptive thresholds measured after 4 days of saline or morphine treatment but prior to hind paw incision. In panel B data are presented representing mechanical nociceptive thresholds in mice undergoing saline or morphine treatment beginning at the time of incision. Nociceptive thresholds were measured immediately before that day's dose of morphine. The statistical analysis presented reflects the results of two-way ANOVA comparing saline/incision values to morphine/incision ones. *p < 0.05, **p < 0.01, N = 6/group.

Mentions: The mechanical nociceptive thresholds for mice at baseline and after 4 days of morphine (chronic morphine) or saline treatment were first measured. In Figure 1A it can be seen that prior to incision morphine treated mice developed mechanical allodynia while saline treated mice had no change in withdrawal thresholds. If no hindpaw incisions were made, morphine pre-treated mice recovered from this allodynia to achieve near baseline withdrawal thresholds over the following 72 hours. Other data in the figure demonstrate that incision, as expected, caused a profound but transient decrease in nociceptive thresholds. While these mice also recovered from the allodynia, mice pretreated with morphine then incised had a slower course of recovery. Specifically, the morphine pretreated/incised mice had lower mechanical withdrawal thresholds than the saline/incised mice at least to 72 hours post-incision.


Chronic morphine administration enhances nociceptive sensitivity and local cytokine production after incision.

Liang D, Shi X, Qiao Y, Angst MS, Yeomans DC, Clark JD - Mol Pain (2008)

Mechanical nociceptive thresholds after drug pretreatment and hindpaw incision. Panel A displays the mechanical thresholds of mice in four different treatment groups: saline pretreatment/no incision, saline pretreatment/incision, morphine pretreatment/no incision, morphine pretreatment/incision. The values labeled pre-incision represent the nociceptive thresholds measured after 4 days of saline or morphine treatment but prior to hind paw incision. In panel B data are presented representing mechanical nociceptive thresholds in mice undergoing saline or morphine treatment beginning at the time of incision. Nociceptive thresholds were measured immediately before that day's dose of morphine. The statistical analysis presented reflects the results of two-way ANOVA comparing saline/incision values to morphine/incision ones. *p < 0.05, **p < 0.01, N = 6/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2279109&req=5

Figure 1: Mechanical nociceptive thresholds after drug pretreatment and hindpaw incision. Panel A displays the mechanical thresholds of mice in four different treatment groups: saline pretreatment/no incision, saline pretreatment/incision, morphine pretreatment/no incision, morphine pretreatment/incision. The values labeled pre-incision represent the nociceptive thresholds measured after 4 days of saline or morphine treatment but prior to hind paw incision. In panel B data are presented representing mechanical nociceptive thresholds in mice undergoing saline or morphine treatment beginning at the time of incision. Nociceptive thresholds were measured immediately before that day's dose of morphine. The statistical analysis presented reflects the results of two-way ANOVA comparing saline/incision values to morphine/incision ones. *p < 0.05, **p < 0.01, N = 6/group.
Mentions: The mechanical nociceptive thresholds for mice at baseline and after 4 days of morphine (chronic morphine) or saline treatment were first measured. In Figure 1A it can be seen that prior to incision morphine treated mice developed mechanical allodynia while saline treated mice had no change in withdrawal thresholds. If no hindpaw incisions were made, morphine pre-treated mice recovered from this allodynia to achieve near baseline withdrawal thresholds over the following 72 hours. Other data in the figure demonstrate that incision, as expected, caused a profound but transient decrease in nociceptive thresholds. While these mice also recovered from the allodynia, mice pretreated with morphine then incised had a slower course of recovery. Specifically, the morphine pretreated/incised mice had lower mechanical withdrawal thresholds than the saline/incised mice at least to 72 hours post-incision.

Bottom Line: Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect.Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesia, Stanford University School of Medicine, Stanford, CA, USA. liang@anesiva.com

ABSTRACT

Background: The chronic use of opioids prior to surgery leads to lowered pain thresholds and exaggerated pain levels after these procedures. Several mechanisms have been proposed to explain this heightened sensitivity commonly termed opioid-induced hyperalgesia (OIH). Most of these proposed mechanisms involve plastic events in the central or peripheral nervous systems. Alterations in the abundance of peripheral mediators of nociception have not previously been explored.

Results: In these experiments mice were treated with saline (control) or ascending daily doses of morphine to generate a state of OIH followed by hind paw incision. In other experiments morphine treatment was initiated at the time of incision. Both mechanical allodynia and peri-incisional skin cytokine levels were measured. Myeloperoxidase (MPO) assays were used to determine neutrophil activity near the wounds. The cytokine production inhibitor pentoxifylline was used to determine the functional significance of the excess cytokines in previously morphine treated animals. Mice treated chronically treated with morphine prior to incision were found to have enhanced skin levels of IL-1beta, IL-6, G-CSF, KC and TNFalpha after incision at one or more time points compared to saline pretreated controls. The time courses of individual cytokines followed different patterns. There was no discernable effect of chronic morphine treatment on wound area neutrophil infiltration. Pentoxifylline reduced cytokine levels and reversed the excess mechanical sensitization caused by chronic morphine administration prior to incision. Morphine treatment initiated at the time of incision did not lead to a generalized enhancement of cytokine production or nociceptive sensitization in excess of the levels observed after incision alone.

Conclusion: The enhanced level of nociceptive sensitization seen after incision in animals chronically exposed to morphine is associated with elevated levels of several cytokines previously reported to be relevant to this incisional pain model. The cytokines may be functional in supporting nociceptive sensitization because pentoxifylline reverses both peri-incisional skin cytokine levels and OIH. Opioid administration beginning at the time of incision does not seem to have the same cytokine enhancing effect. Approaches to postoperative pain control involving a reduction of cytokines may be an effective way to control excessive pain in patients chronically using opioids prior to surgical procedures.

Show MeSH
Related in: MedlinePlus