Examination of sex and minocycline treatment on acute morphine-induced analgesia and inflammatory gene expression along the pain pathway in Sprague–Dawley rats

Biology of Sex Differences

Jaclyn M. Schwarz¹  Staci D. Bilbo²  Laurne S. Terasaki¹  Caitlin K. Posillico¹ 

[1]Department of Psychological and Brain Sciences, University of Delaware, 108 Wolf Hall, Newark 19716, DE, USA

[2]Department of Psychology and Neuroscience, Duke University, 572 Research Dr., Durham 27708, NC, USA

关键词: Analgesia;    Sex;    Minocycline;    Astrocytes;    Microglia;    Morphine;   

Others  :  1234982
DOI  :  10.1186/s13293-015-0049-3

 received in 2015-07-14, accepted in 2015-12-01,  发布年份 2015

【 摘 要 】

Background

In addition to its classical effects on opioid receptors, morphine can activate glia and stimulate the production of pro-inflammatory immune molecules which in turn counteract the analgesic properties of morphine. We hypothesized that decreased morphine analgesia in females may be the result of exaggerated microglial activation in brain regions critical for analgesia.

Methods

Male and female rats were treated with morphine and/or minocycline and morphine analgesia was examined using the hot plate. We also examined the expression of microglial and astrocyte markers in the pain pathway.

Results

Males treated with minocycline, a microglial inhibitor, exhibited a significant increase in acute morphine analgesia as previously shown; however, morphine analgesia was not affected by minocycline pretreatment in female rats. Minocycline decreased the expression of glial activation markers in the male spinal cord and periaqueductal gray as expected; however, these same molecules were upregulated in the female.

Conclusions

These data describe a significant difference between males and females in the behavioral effects following co-administration of morphine and minocycline.

【 授权许可】

   
2015 Posillico et al.

【 图 表 】

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【 参考文献 】

• [1]Baamonde AI, Hidalgo A, Andres-Trelles F. Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology. 1989; 28(9):967-70.
• [2]Bodnar RJ, Romero MT, Kramer E. Organismic variables and pain inhibition: roles of gender and aging. Brain Res Bull. 1988; 21(6):947-53.
• [3]Loyd DR, Wang X, Murphy AZ. Sex differences in micro-opioid receptor expression in the rat midbrain periaqueductal gray are essential for eliciting sex differences in morphine analgesia. J Neurosci. 2008; 28(52):14007-17.
• [4]Craft RM, Stratmann JA, Bartok RE, Walpole TI, King SJ. Sex differences in development of morphine tolerance and dependence in the rat. Psychopharmacology (Berl). 1999; 143(1):1-7.
• [5]Loyd DR, Morgan MM, Murphy AZ. Sexually dimorphic activation of the periaqueductal gray-rostral ventromedial medullary circuit during the development of tolerance to morphine in the rat. Eur J Neurosci. 2008; 27(6):1517-24.
• [6]Bolton JL, Huff NC, Smith SH, Mason SN, Foster WM, Auten RL et al.. Maternal stress and effects of prenatal air pollution on offspring mental health outcomes in mice. Environ Health Perspect. 2013; 121(9):1075-82.
• [7]Levesque S, Taetzsch T, Lull ME, Johnson JA, McGraw C, Block ML. The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function. J Neurochem. 2013; 125(5):756-65.
• [8]Levesque S, Taetzsch T, Lull ME, Kodavanti U, Stadler K, Wagner A et al.. Diesel exhaust activates and primes microglia: air pollution, neuroinflammation, and regulation of dopaminergic neurotoxicity. Environ Health Perspect. 2011; 119(8):1149-55.
• [9]Sekine Y, Ouchi Y, Sugihara G, Takei N, Yoshikawa E, Nakamura K et al.. Methamphetamine causes microglial activation in the brains of human abusers. J Neurosci. 2008; 28(22):5756-61.
• [10]Thomas DM, Dowgiert J, Geddes TJ, Francescutti-Verbeem D, Liu X, Kuhn DM. Microglial activation is a pharmacologically specific marker for the neurotoxic amphetamines. Neurosci Lett. 2004; 367(3):349-54.
• [11]Wang X, Loram LC, Ramos K, de Jesus AJ, Thomas J, Cheng K et al.. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012; 109(16):6325-30.
• [12]Hutchinson MR, Coats BD, Lewis SS, Zhang Y, Sprunger DB, Rezvani N et al.. Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia. Brain Behav Immun. 2008; 22(8):1178-89.
• [13]Hutchinson MR, Northcutt AL, Hiranita T, Wang X, Lewis SS, Thomas J et al.. Opioid activation of toll-like receptor 4 contributes to drug reinforcement. J Neurosci. 2012; 32(33):11187-200.
• [14]Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci. 2009; 30(11):581-91.
• [15]Williamson LL, Sholar PW, Mistry RS, Smith SH, Bilbo SD. Microglia and memory: modulation by early-life infection. J Neurosci. 2011; 31(43):15511-21.
• [16]Schwarz JM, Hutchinson MR, Bilbo SD. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J Neurosci. 2011; 31(49):17835-47.
• [17]Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW et al.. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci. 2008; 28(1):20-9.
• [18]Chen X, Geller EB, Rogers TJ, Adler MW. The chemokine CX3CL1/fractalkine interferes with the antinociceptive effect induced by opioid agonists in the periaqueductal grey of rats. Brain Res. 2007; 1153:52-7.
• [19]Barrett AC, Cook CD, Terner JM, Craft RM, Picker MJ. Importance of sex and relative efficacy at the mu opioid receptor in the development of tolerance and cross-tolerance to the antinociceptive effects of opioids. Psychopharmacology (Berl). 2001; 158(2):154-64.
• [20]Cicero TJ, Nock B, Meyer ER. Sex-related differences in morphine’s antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther. 1997; 282(2):939-44.
• [21]Craft RM. Sex differences in drug- and non-drug-induced analgesia. Life Sci. 2003; 72(24):2675-88.
• [22]Craft RM. Sex differences in opioid analgesia: “from mouse to man”. Clin J Pain. 2003; 19(3):175-86.
• [23]Okamoto K, Tashiro A, Hirata H, Bereiter DA. Differential modulation of TMJ neurons in superficial laminae of trigeminal subnucleus caudalis/upper cervical cord junction region of male and cycling female rats by morphine. Pain. 2005; 114(1–2):203-11.
• [24]Wang X, Traub RJ, Murphy AZ. Persistent pain model reveals sex difference in morphine potency. Am J Physiol Regul Integr Comp Physiol. 2006; 291(2):R300-6.
• [25]Eidson LN, Murphy AZ. Blockade of toll-like receptor 4 attenuates morphine tolerance and facilitates the pain relieving properties of morphine. J Neurosci. 2013; 33(40):15952-63.
• [26]Eidson LH, Murphy AZ. Persistent peripheral inflammation attenuates morphine-induced periaqueductal gray glial cell activation and analgesic tolerance in the male rat. J Pain. 2013; 4:393-404.
• [27]Hutchinson MR, Northcutt AL, Chao LW, Kearney JJ, Zhang Y, Berkelhammer DL et al.. Minocycline suppresses morphine-induced respiratory depression, suppresses morphine-induced reward, and enhances systemic morphine-induced analgesia. Brain Behav Immun. 2008; 22(8):1248-56.
• [28]Zychowska M, Rojewska E, Kreiner G, Nalepa I, Przewlocka B, Mika J. Minocycline influences the anti-inflammatory interleukins and enhances the effectiveness of morphine under mice diabetic neuropathy. J Neuroimmunol. 2013; 262(1–2):35-45.
• [29]Pabon MM, Bachstetter AD, Hudson CE, Gemma C, Bickford PC. CX3CL1 reduces neurotoxicity and microglial activation in a rat model of parkinson’s disease. J Neuroinflammation. 2011; 8:9.
• [30]Zujovic V, Benavides J, Vige X, Carter C, Taupin V. Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia. 2000; 29(4):305-15.
• [31]Clark AK, Malcangio M. Fractalkine/CX3CR1 signaling during neuropathic pain. Front Cell Neurosci. 2014;8. doi:10.3389/fncel.2014.00121.
• [32]Milligan ED, Sloane EM, Watkins L. Glia in pathological pain: a role for fractalkine. J Neuroimmunol. 2008; 198(1–2):113-20.
• [33]Kobayashi K, Imagama S, Ohgomori T, Hirano K, Uchimura K, Sakamoto K et al.. Minocycline selectively inhibits M1 polarization of microglia. Cell Death Dis. 2013; 4:e525.
• [34]Ryu JK, Franciosi S, Sattayaprasert P, Kim SU, McLarnon JG. Minocycline inhibits neuronal death and glial activation induced by beta-amyloid peptide in rat hippocampus. Glia. 2004; 48(1):85-90.
• [35]Ryu JK, McLarnon JG. Minocycline or iNOS inhibition block 3-nitrotyrosine increases and blood–brain barrier leakiness in amyloid beta-peptide-injected rat hippocampus. Exp Neurol. 2006; 198(2):552-7.
• [36]Li J, McCullough LD. Sex differences in minocycline-induced neuroprotection after experimental stroke. J Cereb Blood Flow Metab. 2009; 29(4):670-4.
• [37]Sorge RE, Mapplebeck JCS, Rosen S, Beggs S, Taves S, Alexander JK, et al. Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015. Doi:. 10. 1038/nn.4053 webcite
• [38]Bastos LF, Godin AM, Zhang Y, Jarussophon S, Ferreira BC, Machado RR et al.. A minocycline derivative reduces nerve injury-induced allodynia, LPS-induced prostaglandin E2 microglial production and signaling via toll-like receptors 2 and 4. Neurosci Lett. 2013; 543:157-62.
• [39]Hoda MN, Li W, Ahmad A, Ogbi S, Zemskova MA, Johnson MH et al.. Sex-independent neuroprotection with minocycline after experimental thromboembolic stroke. Exp Transl Stroke Med. 2011; 3(1):16.
• [40]Loyd DR, Murphy AZ. Sex differences in the anatomical and functional organization of the periaqueductal gray-rostral ventromedial medullary pathway in the rat: a potential circuit mediating the sexually dimorphic actions of morphine. J Comp Neurol. 2006; 496(5):723-38.
• [41]Chakrabarti S, Liu NJ, Gintzler AR. Formation of mu-/kappa-opioid receptor heterodimer is sex-dependent and mediates female-specific opioid analgesia. Proc Natl Acad Sci U S A. 2010; 107(46):20115-9.
• [42]Gintzler AR, Schnell SA, Gupta DS, Liu NJ, Wessendorf MW. Relationship of spinal dynorphin neurons to delta-opioid receptors and estrogen receptor alpha: anatomical basis for ovarian sex steroid opioid antinociception. J Pharmacol Exp Ther. 2008; 326(3):725-31.
• [43]Kepler KL, Kest B, Kiefel JM, Cooper ML, Bodnar RJ. Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav. 1989; 34(1):119-27.
• [44]Liu NJ, Chakrabarti S, Schnell S, Wessendorf M, Gintzler AR. Spinal synthesis of estrogen and concomitant signaling by membrane estrogen receptors regulate spinal kappa- and mu-opioid receptor heterodimerization and female-specific spinal morphine antinociception. J Neurosci. 2011; 31(33):11836-45.
• [45]Liu NJ, Schnell S, Wessendorf MW, Gintzler AR. Sex, pain, and opioids: Interdependent influences of sex and pain modality on dynorphin-mediated antinociception in rats. J Pharmacol Exp Ther. 2013; 344(2):522-30.
• [46]Liu N, Gintzler AR. Spinal endomorphin 2 antinociception and the mechanisms that produce it are both sex- and stage of estrus Cycle–Dependent in rats. J Pain. 2013; 14(11):1522-30.
• [47]Cataldo G, Lovric J, Chen C, Pytte CL, Bodnar RJ. Ventromedial and medial preoptic hypothalamic ibotenic acid lesions potentiate systemic morphine analgesia in female, but not male rats. Behav Brain Res. 2010; 214(2):301-16.
• [48]Krzanowska EK, Bodnar RJ. Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res. 1999; 821(1):224-30.
• [49]Krzanowska EK, Bodnar RJ. Analysis of sex and gonadectomy differences in β-endorphin antinociception elicited from the ventrolateral periaqueductal gray in rats. Eur J Pharmacol. 2000; 392(3):157-61.
• [50]Krzanowska EK, Ogawa S, Pfaff DW, Bodnar RJ. Reversal of sex differences in morphine analgesia elicited from the ventrolateral periaqueductal gray in rats by neonatal hormone manipulations. Brain Res. 2002; 929(1):1-9.
• [51]Krzanowska EK, Znamensky V, Wilk S, Bodnar RJ. Antinociceptive and behavioral activation responses elicited by d-Pro2-endomorphin-2 in the ventrolateral periaqueductal gray are sensitive to sex and gonadectomy differences in rats☆. Peptides. 2000; 21(5):705-15.
• [52]Sorge RE, LaCroix-Fralish ML, Tuttle AH, Sotocinal SG, Austin J, Ritchie J et al.. Spinal cord toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci. 2011; 31(43):15450-4.
• [53]Loram LC, Sholar PW, Taylor FR, Wiesler JL, Babb JA, Strand KA, Berkelhammer D, Day HE, Maier SF, Watkins LR. Sex and estradiol influence glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology. 2012; 37(10):1688-99.