Chronic pain affects one third of the adult population and presents a massive societal and economic burden. Current treatment approaches typically include non-steroidal anti-inflammatory drugs that suffer from limited efficacy and opioids, which possess significant addiction liability. Consequently, there is an urgent need to identify novel drug targets to facilitate the development of non-addictive analgesics to treat chronic pain. The endocannabinoid anandamide (AEA) activates cannabinoid receptors while the related lipid palmitoylethanolamide (PEA) serves as an agonist at peroxisome proliferator-activated receptor alpha (PPAR?). Activation of cannabinoid receptors by AEA or PPAR? receptors by PEA reduces pain, thus positioning modulation of AEA and PEA signaling as an attractive strategy for the development of analgesics. Our group recently identified fatty acid binding protein 5 (FABP5) as an intracellular carrier for AEA and PEA, whose inhibition elevates AEA and PEA levels and produces analgesia. In addition to its expression in the brain, FABP5 is enriched in peripheral sensory neurons and macrophages, positioning it in cell populations that promote pain. Transient receptor potential vanilloid receptor 1 (TRPV1) is an ion channel expressed in peripheral sensory neurons that is essential for inflammatory thermal hyperalgesia and is implicated in diverse pain conditions in humans. Here, we will test the novel hypothesis that FABP5 inhibition potentiates AEA and PEA signaling in sensory neurons to suppress pain by attenuating the sensitization and upregulation of TRPV1 during inflammation.
Specific Aim 1 will test the hypothesis that genetic deletion of FABP5 in sensory neurons unmasks analgesic effects mediated by AEA and PEA while its deletion in macrophages suppresses pain by attenuating the pro-inflammatory output of macrophages. To interrogate the mechanisms underlying these effects, Specific Aim 2 will test the hypothesis that TRPV1 sensitization, a process that amplifies inflammatory pain, is suppressed in mice lacking FABP5. We will further determine whether this effect is mediated by augmented AEA and PEA signaling in sensory neurons.
Specific Aim 3 will test the hypothesis that FABP5 is essential for TRPV1 upregulation during chronic inflammation. Specifically, we will investigate the molecular mechanisms underlying the control of TRPV1 upregulation by FABP5 in sensory neurons. If successful, the outcome of this work will advance our understanding of pain modulation by FABP5, AEA, and PEA, and will provide a foundation for the development of analgesics targeting FABP5.

Public Health Relevance

The increasing use of opioids for the treatment of chronic pain has contributed to a dramatic rise in prescription opioid abuse and addiction, highlighting the urgent need to develop novel efficacious non-addictive analgesics. Fatty acid binding proteins regulate the metabolism and signaling of lipids that suppress pain and the goal of this project is to identify the mechanisms through which fatty acid binding protein inhibition produces analgesic effects. The outcome of this study will elucidate the cellular and molecular mechanisms underlying pain modulation by fatty acid binding proteins, which may lead to the development of novel analgesics.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
Zip Code
Blum, Kenneth; Modestino, Edward J; Badgaiyan, Rajendra D et al. (2018) Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse. EC Psychol Psychiatr 7:564-579
Hamilton, John; Marion, Matthew; Figueiredo, Antonio et al. (2018) Fatty acid binding protein deletion prevents stress-induced preference for cocaine and dampens stress-induced corticosterone levels. Synapse 72:e22031
Blum, K; Jacobs, W; Modestino, E J et al. (2018) Insurance Companies Fighting the Peer Review Empire without any Validity: the Case for Addiction and Pain Modalities in the face of an American Drug Epidemic. SEJ Surg Pain 1:1-11
Haj-Dahmane, Samir; Shen, Roh-Yu; Elmes, Matthew W et al. (2018) Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses. Proc Natl Acad Sci U S A 115:3482-3487
Bogdan, Diane; Falcone, Jerome; Kanjiya, Martha P et al. (2018) Fatty acid-binding protein 5 controls microsomal prostaglandin E synthase 1 (mPGES-1) induction during inflammation. J Biol Chem 293:5295-5306
Chakraborty, Saikat; Elvezio, Vincent; Kaczocha, Martin et al. (2017) Presynaptic inhibition of transient receptor potential vanilloid type 1 (TRPV1) receptors by noradrenaline in nociceptive neurons. J Physiol 595:2639-2660
Hsu, Hao-Chi; Tong, Simon; Zhou, Yuchen et al. (2017) The Antinociceptive Agent SBFI-26 Binds to Anandamide Transporters FABP5 and FABP7 at Two Different Sites. Biochemistry 56:3454-3462
Figueiredo, Antonio; Hamilton, John; Marion, Matthew et al. (2017) Pharmacological Inhibition of Brain Fatty Acid Binding Protein Reduces Ethanol Consumption in Mice. J Reward Defic Syndr Addict Sci 3:21-27
Peng, Xiaoxue; Studholme, Keith; Kanjiya, Martha P et al. (2017) Fatty-acid-binding protein inhibition produces analgesic effects through peripheral and central mechanisms. Mol Pain 13:1744806917697007
Martin, Gregory G; Chung, Sarah; Landrock, Danilo et al. (2016) Female Mice are Resistant to Fabp1 Gene Ablation-Induced Alterations in Brain Endocannabinoid Levels. Lipids 51:1007-20

Showing the most recent 10 out of 20 publications