Opioid drugs, such as morphine, are widely prescribed for the treatment of moderate to severe pain. While morphine and other opioids are the most effective treatment of pain, they do not provide adequate pain relief for all. For others, treatment of pain with opioids can lead down a path of dependence and addiction. An individual's sex is one major factor in determining the effectiveness of opioids for the reduction of pain and the potential for abuse liability. In both the human and the rodent literature, it has been demonstrated that males experience greater analgesia than females after opioid administration. In contrast, the rewarding properties of morphine are much greater in females than in males. Searching for a common mechanism for such disparate effects of sex on morphine-induced analgesia and reward has been difficult. However, recent evidence indicates that a critical component of morphine effectiveness involves the direct activation of microglia in the brain via the innate immune system's pattern recognition receptor, toll-like receptor (TLR) 4. This morphine-induced activation of microglia in the brain initiates the release of pro-inflammatory cytokines that markedly increase opioid-induced reward, tolerance and dependence and simultaneously decrease opioid analgesia. We therefore hypothesize that morphine-induced activation of microglia is significantly greater in females compared to males, and this glial activation may be an underlying mechanism for the differential effects of sex on morphine-induced analgesia and reward. The major objectives of this proposal are three-fold;1) to understand basic sex differences in immune activation upon morphine treatment;2) to understand the potential role of morphine-induced glial activation in sex differences in morphine-induced analgesia and abuse liability;and 3) to establish the specific role of microglia and begin to determine potential mechanisms.

Public Health Relevance

The sex of an individual is a major factor in determining the effectiveness of opioid analgesia. The results of this proposal will lend insight into the role that the immune system plays in the effectiveness of morphine, as well as the potential for drug abuse between the sexes. Understanding how drugs affect males and females differently is a first step in the quest for personalized medicine.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F02A-J (20))
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Avila, Albert
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Duke University
Schools of Arts and Sciences
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Posillico, Caitlin K; Terasaki, Laurne S; Bilbo, Staci D et al. (2015) Examination of sex and minocycline treatment on acute morphine-induced analgesia and inflammatory gene expression along the pain pathway in Sprague-Dawley rats. Biol Sex Differ 6:33
Schwarz, Jaclyn M; Bilbo, Staci D (2013) Adolescent morphine exposure affects long-term microglial function and later-life relapse liability in a model of addiction. J Neurosci 33:961-71
Schwarz, Jaclyn M; Smith, Susan H; Bilbo, Staci D (2013) FACS analysis of neuronal-glial interactions in the nucleus accumbens following morphine administration. Psychopharmacology (Berl) 230:525-35
Bilbo, Staci D; Schwarz, Jaclyn M (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33:267-86
Schwarz, Jaclyn M; Bilbo, Staci D (2012) Sex, glia, and development: interactions in health and disease. Horm Behav 62:243-53
Schwarz, Jaclyn M; Sholar, Paige W; Bilbo, Staci D (2012) Sex differences in microglial colonization of the developing rat brain. J Neurochem 120:948-63
Schwarz, Jaclyn M; Hutchinson, Mark R; Bilbo, Staci D (2011) 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 31:17835-47
Schwarz, Jaclyn M; Bilbo, Staci D (2011) LPS elicits a much larger and broader inflammatory response than Escherichia coli infection within the hippocampus of neonatal rats. Neurosci Lett 497:110-5