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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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Mechanical allodynia after incision as affected by morphine and pentoxifylline. In these experiments mice were subjected to nociceptive testing of the hind paw to establish the baseline threshold. Mice were then pre-treated with either saline or morphine for 4 days prior to hind paw incisions being made. After incision, groups of mice were treated daily with daily intraperitoneal saline or pentoxifylline as described in Methods. Nociceptive testing 72 hours after hind paw incision (2 hours after the last dose of pentoxifylline). **p < 0.01, N = 8/group.
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Figure 5: Mechanical allodynia after incision as affected by morphine and pentoxifylline. In these experiments mice were subjected to nociceptive testing of the hind paw to establish the baseline threshold. Mice were then pre-treated with either saline or morphine for 4 days prior to hind paw incisions being made. After incision, groups of mice were treated daily with daily intraperitoneal saline or pentoxifylline as described in Methods. Nociceptive testing 72 hours after hind paw incision (2 hours after the last dose of pentoxifylline). **p < 0.01, N = 8/group.

Mentions: While we had observed to this point a correlation between incision area cytokine levels and the enhancement in post-incision allodynia caused by chronic morphine administration, we had no functional evidence for the participation of these substances. We therefore administered the broad spectrum cytokine production inhibitor pentoxifylline on a daily basis after incisions were made. The pentoxifylline dose (50 mg/kg) and daily injection schedule chosen for these experiments has been shown by others to reduce nociceptive sensitization in mouse and rat models of neuropathic pain [37,38]. In Figure 5 data are presented demonstrating that pentoxifylline administered daily after the time of hind paw incision completely eliminated the morphine-enhancement of nociception normally observed at 72 hours. There was no effect on the mechanical nociceptive thresholds of mice that underwent hind paw incision after chronic saline pretreatment. In additional experiments we observed that pentoxifylline reduced skin cytokine levels 72 hours after incision in morphine pretreated mice. The levels were reduced by 74%, 55% and 53% for G-CSF, IL-1β and KC respectively (p < 0.05 vs. vehicle-treated mice). For IL-6 and TNFα, pentoxifylline failed to significantly reduce cytokine levels.


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 allodynia after incision as affected by morphine and pentoxifylline. In these experiments mice were subjected to nociceptive testing of the hind paw to establish the baseline threshold. Mice were then pre-treated with either saline or morphine for 4 days prior to hind paw incisions being made. After incision, groups of mice were treated daily with daily intraperitoneal saline or pentoxifylline as described in Methods. Nociceptive testing 72 hours after hind paw incision (2 hours after the last dose of pentoxifylline). **p < 0.01, N = 8/group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Mechanical allodynia after incision as affected by morphine and pentoxifylline. In these experiments mice were subjected to nociceptive testing of the hind paw to establish the baseline threshold. Mice were then pre-treated with either saline or morphine for 4 days prior to hind paw incisions being made. After incision, groups of mice were treated daily with daily intraperitoneal saline or pentoxifylline as described in Methods. Nociceptive testing 72 hours after hind paw incision (2 hours after the last dose of pentoxifylline). **p < 0.01, N = 8/group.
Mentions: While we had observed to this point a correlation between incision area cytokine levels and the enhancement in post-incision allodynia caused by chronic morphine administration, we had no functional evidence for the participation of these substances. We therefore administered the broad spectrum cytokine production inhibitor pentoxifylline on a daily basis after incisions were made. The pentoxifylline dose (50 mg/kg) and daily injection schedule chosen for these experiments has been shown by others to reduce nociceptive sensitization in mouse and rat models of neuropathic pain [37,38]. In Figure 5 data are presented demonstrating that pentoxifylline administered daily after the time of hind paw incision completely eliminated the morphine-enhancement of nociception normally observed at 72 hours. There was no effect on the mechanical nociceptive thresholds of mice that underwent hind paw incision after chronic saline pretreatment. In additional experiments we observed that pentoxifylline reduced skin cytokine levels 72 hours after incision in morphine pretreated mice. The levels were reduced by 74%, 55% and 53% for G-CSF, IL-1β and KC respectively (p < 0.05 vs. vehicle-treated mice). For IL-6 and TNFα, pentoxifylline failed to significantly reduce cytokine levels.

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