Limits...
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.

Show MeSH

Related in: MedlinePlus

Myeloperoxidase (MPO) activity after hind paw incisions. For these experiments MPO activity was measured in peri-incisional skin as an index of infiltrating neutrophil activity. Skin was harvested from separate groups of mice at the indicated time points and processed for MPO assays as described in Methods. The time course for analysis was the same as that used for the behavioral and cytokine assays. Statistical analysis failed to detect between group differences at any of these time points. N = 8/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2279109&req=5

Figure 4: Myeloperoxidase (MPO) activity after hind paw incisions. For these experiments MPO activity was measured in peri-incisional skin as an index of infiltrating neutrophil activity. Skin was harvested from separate groups of mice at the indicated time points and processed for MPO assays as described in Methods. The time course for analysis was the same as that used for the behavioral and cytokine assays. Statistical analysis failed to detect between group differences at any of these time points. N = 8/group.

Mentions: Because infiltrating neutrophils are a potential source of cytokines in incisional wounds and because acute morphine administration can alter neutrophil infiltration [31], we sought to determine whether the morphine-related differences in cytokine levels were attributable to differences in the peri-incisional levels of these infiltrating cells. We chose for these measurements the myeloperoxidase assay (MPO) which has excellent correlation with immunohistochemical neutrophil counts in these mouse hind paw incisions [31]. In Figure 4 data are presented showing that incising the hind paw does lead to a rapid but transient rise in neutrophil skin abundance. However, chronic morphine pretreatment did not significantly alter the degree of infiltration when compared with saline pretreated mice. Specifically, MPO levels were not higher in the skin of morphine treated then incised skin when compared with saline treated then incised skin at the 2, 24 or 72 hour time points when the levels of specific cytokines were enhanced (Figure 2).


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)

Myeloperoxidase (MPO) activity after hind paw incisions. For these experiments MPO activity was measured in peri-incisional skin as an index of infiltrating neutrophil activity. Skin was harvested from separate groups of mice at the indicated time points and processed for MPO assays as described in Methods. The time course for analysis was the same as that used for the behavioral and cytokine assays. Statistical analysis failed to detect between group differences at any of these time points. N = 8/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Myeloperoxidase (MPO) activity after hind paw incisions. For these experiments MPO activity was measured in peri-incisional skin as an index of infiltrating neutrophil activity. Skin was harvested from separate groups of mice at the indicated time points and processed for MPO assays as described in Methods. The time course for analysis was the same as that used for the behavioral and cytokine assays. Statistical analysis failed to detect between group differences at any of these time points. N = 8/group.
Mentions: Because infiltrating neutrophils are a potential source of cytokines in incisional wounds and because acute morphine administration can alter neutrophil infiltration [31], we sought to determine whether the morphine-related differences in cytokine levels were attributable to differences in the peri-incisional levels of these infiltrating cells. We chose for these measurements the myeloperoxidase assay (MPO) which has excellent correlation with immunohistochemical neutrophil counts in these mouse hind paw incisions [31]. In Figure 4 data are presented showing that incising the hind paw does lead to a rapid but transient rise in neutrophil skin abundance. However, chronic morphine pretreatment did not significantly alter the degree of infiltration when compared with saline pretreated mice. Specifically, MPO levels were not higher in the skin of morphine treated then incised skin when compared with saline treated then incised skin at the 2, 24 or 72 hour time points when the levels of specific cytokines were enhanced (Figure 2).

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