Open Access Open Access  Restricted Access Subscription or Fee Access

Opioid treatment of experimental pain activates nuclear factor-κB

Peggy Compton, RN, PhD, Charles Griffis, CRNA, PhD, Elizabeth Crabb Breen, PhD, Matthew Torrington, MD, Ryan Sadakane, BS, Eshetu Tefera, MS, Michael R. Irwin, MD

Abstract


Objective: To determine the independent and combined effects of pain and opioids on the activation of an early marker of inflammation, nuclear factor-κB (NF-κB).

Design: NF-κB activation was compared within-subjects following four randomly ordered experimental sessions of opioid-only (intravenous fentanyl 1 μg/kg), pain-only (cold-pressor), opioid + pain, and a resting condition.

Setting: University General Clinical Research Center.

Participants: Twenty-one (11 female) healthy controls.

Interventions: Following exposure to treatment (fentanyl administration and/or cold-pressor pain), blood samples for NF-kB analysis were obtained.

Main outcome measures: Intracellular levels of activated NF-κB, in unstimulated and stimulated peripheral blood mononuclear cells at 15 and 30 minutes.

Results: Neither pain nor opioid administration alone effected NF-κB levels in cell populations; however, the combination of treatments induced significant increases of NF-κB in stimulated peripheral blood mononuclear cell, lymphocytes, and monocytes.

Conclusions: The combination of acute pain with opioids, as occurs in clinical situations, activates a key transcription factor involved in proinflammatory responses.


Keywords


pain, opioids, NF-B, cold-pressor test, fentanyl

Full Text:

PDF

References


Hutchinson MR, Coats BD, Lewis SS, et al.: Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008; 22(8): 1178-1189.

Ren K, Dubner R: Interactions between the immune and nervous systems in pain. Nat Med. 2010; 16(11): 1267-1276.

Greisen J, Juhl C, Grofte T, et al.: Acute pain induces insulin resistance in humans. Anesthesiology. 2001; 95(3): 578-584.

Lutgendorf SK, Logan H, Costanzo E, et al.: Effects of acute stress, relaxation, and a neurogenic inflammatory stimulus on interleukin-6 in humans. Brain Behav Immun. 2004; 18(1): 55-64.

Griffis CA, Irwin MR, Martinez-Maza O, et al.: Pain-related activation of leukocyte cellular adhesion molecules: Preliminary findings. Neuroimmunomodulation. 2007; 14(5): 224-228.

Edwards RR, Kronfli T, Haythornwaite JA, et al.: Association of catastrophizing with interleukin-6 responses to acute pain. Pain. 2008; 140(10): 135-144.

Hutchinson MR, Bland ST, Johnson KW, et al.: Opioid-induced glial activation: Mechanisms of activation, dependence, and reward. Sci World J. 2007; 7: 98-111.

Griffis CA, Crabb Breen E, Compton P, et al.: Acute painful stress and inflammatory mediator production. Neuroimmunomodulation. 2013; 20(3): 127-133.

Rang HP, Dale MM, Henderson G: Analgesic drugs. In Rang & Dale’s Pharmacology. 7th ed. London: Churchill Livingstone, 2011: 503-524.

Schumacher MA, Bausbaum A, Way WL: Opioid analgesics and antagonists. In Katzung B, Masters S, Trevor A (eds.): Basic and Clinical Pharmacology. 12th ed. New York, NY: McGraw Hill Companies, 2012: 543-564.

Beilin B, Shavit Y, Hart J, et al.: Effects of anesthesia based on large vs. small doses of fentanyl on natural killer cell cytotoxicity in the perioperative period. Anesth Analg. 1996; 82(3): 492-497.

Hall DM, Suo JL, Weber RJ: Opioid mediated effects on the immune system: Sympathetic nervous system involvement. J Neuroimmunol. 1998; 83(1-2: 29-35.

McCarthy L, Wetzel M, Sliker JK, et al.: Opioids, opioid receptors, and the immune response. Drug Alcohol Depend. 2001; 62(2): 111-123.

Bussiere JL, Adler MW, Rogers TJ, et al.: Cytokine reversal of morphine-induced suppression of the antibody response. J Pharmacol Exp Ther. 1993; 264(2): 591-597.

Eisenstein EM, Jaffe JS, Strober W: Reduced interleukin-2 (IL-2) production in common variable immunodeficiency is due to a primary abnormality of CD4+ T cell differentiation. J Clin Immunol. 1993; 13(4): 247-258.

Martin-Kleiner I, Balog T, Gabrilovac J: Signal transduction induced by opioids in immune cells: A review. Neuroimmunomodulation. 2006; 13(1): 1-77.

Bastami S, Norling C, Trinks C, et al.: Inhibitory effect of opiates on LPS mediated release of TNF and IL-8. Acta Oncol. 2013; 52(5): 1022-1033.

Börner C, Kraus J: Inhibition of NF-B by opioids in T cells. J Immunol. 2013; 191(9): 4640-4647.

Mizota T, Tsujikawa H, Shoda T, et al.: Dual modulation of the T-cell receptor-activated signal transduction pathway by morphine in human T lymphocytes. J Anesth. 2013; 27(1): 80-87.

Brack A, Rittner HL, Stein C: Immunosuppressive effects of opioids—Clinical relevance. J Neuroimmune Pharmacol. 2011; 6(4): 490-502.

Al-Hashimi M, Scott SW, Thompson JP, et al.: Opioids and immune modulation: more questions than answers. Br J Anaesth. 2013; 111(1): 80-88.

Ninkovic´ J, Roy S: Role of the mu-opioid receptor in opioid modulation of immune function. Amino Acids. 2013; 45(1): 9-24.

Hawkley L, Cacioppo J: Stress and the aging immune system. Brain Behav Immun. 2004; 18: 114-119.

Krichevsky S, Pawelee G, Gural A, et al.: Age related microsatellite instability in T cells from healthy individuals. Exp Gerontol. 2004; 39(4): 507-515.

Walker DJ, Zancy JP: Subjective, psychomotor, and physiological effects of cumulative doses of opioid mu agonists in healthy volunteers. J Pharmacol Exp Ther. 1999; 289(3): 1454-1464.

Eckhardt K, Li S, Ammon S, et al.: Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formulation. Pain. 1998; 76(1-2): 27-33.

Wolff BB, Kantor TG, Cohen P: Laboratory pain induction methods for human analgesic assays. In Bonica JJ, Albe-Fessard D (eds.): Advances in Pain Research and Therapeutics. 1st ed. New York: Raven Press, 1976: 363-367.

Garcia de Jalon PD, Harrison FJ, Johnson KI, et al.: A modified cold stimulation technique for the evaluation of analgesic activity in human volunteers. Pain. 1985; 22(2): 183-189.

Davis KD, Pope GE: Noxious cold evokes multiple sensations with distinct time courses. Pain. 2002; 98(1-2): 179-185.

Cruz-Almeida Y, King CD, Wallet SM, et al.: Immune biomarker response depends on choice of experimental pain stimulus in healthy adults: A preliminary study. Pain Res Treat. 2012; 2012.

Goodin BR, Quinn NB, King CD, et al.: Salivary cortisol and soluble tumor necrosis factor-receptor II responses to multiple experimental modalities of acute pain. Psychophysiology. 2012; 49(1): 118-127.

Pace TW, Mletzko TC, Alagbe O, et al.: Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006; 163(9): 1630-1633.

Robertson D, Johnson GA, Robertson RM, et al.: Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation. 1979; 59(4): 637-643.

Stratton JR, Halter JB, Hallstrom AP, et al.: Comparative plasma catecholamine and hemodynamic responses to handgrip, cold pressor and supine bicycle exercise testing in normal subjects. J Am Coll Cardiol. 1983; 2(1): 93-104.

Goodin BR, Quinn NR, Kronfli T, et al.: Experimental pain ratings and reactivity of cortisol and soluble tumor necrosis factor-receptor II following a trial of hypnosis: Results of a randomized controlled pilot study. Pain Med. 2012; 13(1): 29-44.

Walsh NE, Schoenfeld L, Ramamurthy S, et al.: Normative mode for cold pressor test. Am J Phys Med Rehabil. 1989; 68(1): 6-11.

Zacny JP, McKay MA, Toledano AY, et al.: The effects of a cold-water immersion stressor on the reinforcing and subjective effects of fentanyl in healthy volunteers. Drug Alcohol Depend. 1996; 42(2): 133-142.

Conley KM, Toledano AY, Apfelbaum JL, et al.: Modulating effects of a cold water stimulus on opioid effects in volunteers. Psychopharmacology (Berl). 1997; 131(4): 313-320.

Lovallo W: The cold pressor test and autonomic function: A review and integration. Psychophysiology. 1975; 12(3): 268-282.

Carroll D, Davey S, Willemsen G, et al.: Blood pressure reactions to the cold pressor test and the prediction of ischaemic heart disease: Data from the Caerphilly Study. J Epidemiol Community Health. 1998; 52(8): 528-529.

Mourot L, Bouhaddi M, Regnard J: Effects of the cold pressor test on cardiac autonomic control in normal subjects. Physiol Res. 2009; 58: 83-91.

Bierhaus A, Wolf J, Andrassy M, et al.: A mechanism converting psychosocial stress into mononuclear cell activation. Proc Natl Acad Sci USA. 2003; 100(4): 1920-1925.

Griffis C, Compton P, Doering L: The effect of pain on leukocyte cellular adhesion molecules. Biol Res Nurs. 2006; 7(4): 297-312.

Zhang LZ, Guo Z: Tramadol reduces myocardial infarct size and expression and activation of nuclear factor kappa B in acute myocardial infarction in rats. Eur J Anaesthesiol. 2009; 26(12): 1048-1055.

Wypasek E, Natorska J, Mazur AI, et al.: Toll-like receptor expression and NF-B activation in peritoneal leukocytes in morphine-mediated impairment of zymosan-induced peritonitis in Swiss mice. Arch Immunol Ther Exp (Warsz). 2012; 60(5); 373-382.

Jan WC, Chen CH, Hsu K, et al.: L-type calcium channels and mu-opioid receptors involved in mediating the anti-inflammatory effects of naloxone. J Surg Res. 2011; 167(2): 263-272.

Roy S, Cain KJ, Chapin RB, et al.: Morphine modulates NF kappa B activation in macrophages. Biochem Biophys Res Commun. 1998; 245(17): 392-396.

Happel C, Kutzler M, Rogers TJ: Opioid-induced chemokine expression requires NF-B activity: the role of PKCz. J Leukoc Biol. 2011; 89(2): 301-309.

Houghtling RA, Mellon RD, Tan RJ, et al.: Acute effects of morphine on blood lymphocyte proliferation and IL-6 levels. Ann N Y Acad Sci. 2000; 917: 771-777.

Pacifici R, di Carlo S, Bacosi A, et al.: Pharmacokinetics and cytokine production in heroin and morphine-treated mice. Int J Immunopharmacol. 2000; 22(8): 603-614.

Holan V, Zajicova A, Krulova M, et al.: Augmented production of proinflammatory cytokines and accelerated allotransplantation reactions in heroin-treated mice. Clin Exp Immunol. 2003; 132(1): 40-45.

Sacerdote P: Effects of in vitro and in vivo opioids on the production of IL-12 and IL-10 by murine macrophages. Ann N Y Acad Sci. 2003; 992: 129-140.

Kelschenbach J, Barke RA, Roy S: Morphine withdrawal contributes to TH cell differentiation by biasing cells toward the TH2 lineage. J Immunol. 2005; 175: 587-595.

Watkins LR, Hutchinson MR, Johnston IN, et al.: Glia: Novel counter-regulators of opioid analgesia. Trends Neurosci. 2005; 28(12): 661-669.

Reyes-Gibby CC, El Osta B, Spitz MR, et al.: The influence of tumor necrosis factor-alpha-308 G/A and IL-6-174 G/C on pain and analgesia response in lung cancer patients receiving supportive care. Cancer Epidemiol Biomarkers Prev. 2008; 17(11): 3262-3267.

Nelson CJ, Lysle DT: Morphine modulation of the contact hypersensitivity response: Characterization of immunological changes. Clin Immunol. 2001; 98(3): 370-377.

Wu Y, Wang Y, Zhan J: Effects of remifentanyl and fentanyl on LPS-induced cytokine release in human whole blood in vitro. Mol Biol Rep. 2009; 36(5): 1113-1117.

Rafati A, Taj SH, Azarpira N, et al.: Chronic morphine consumption increase allograft rejection rate in rat through inflammatory reactions. Iran Biomed J. 2011; 15(3): 85-91.

Hyejin J, Mei L, Seongheon L, et al.: Remifentanil attenuates human neutrophil activation induced by lipopolysaccharide. Immunopharmacol Immunotoxicol. 2013; 35(2): 264-271.

Joshi GP, Beck DE, Emerson RH, et al.: Defining new directions for more effective management of surgical pain in the United States: Highlights of the inaugural Surgical Pain Congress™. Am Surg. 2014; 80(3): 219-228.

Vadivelu N, Mitra S, Narayan D: Recent advances in postoperative pain management. Yale J Biol Med. 2010; 83(1): 11-25.

Viscusi ER, Pappagallo M: A review of opioids for in-hospital pain management. Hosp Pract (1995). 2012; 40(1): 149-159.




DOI: https://doi.org/10.5055/jom.2015.0261

Refbacks

  • There are currently no refbacks.