Abstract To date, ~1.1 million people in the United State and ~37 million people worldwide are infected with the human immunodeficiency virus (HIV). Of those infected with HIV, almost a third experience distal symmetric polyneuropathy often associated with neuropathic pain. While opioids are currently the cornerstone medication for treating severe pain in these patients, they can paradoxically lead to an increase in sensitivity to noxious stimuli (opioid-induced hyperalgesia) as well as an exacerbation of HIV-associated clinical pain. The precise mechanisms by which opioids interact with the viral infection to exacerbate neuropathic pain have yet to be fully elucidated, but likely involve the synergetic dysregulation of neuro-glial interactions, including glial activation and alterations in the excitation-inhibition balance of the brain. Despite the rapid accumulation of preclinical studies investigating these mechanisms, human evidence is currently lacking. To evaluate the role of neuro-glial dysregulation as a mechanism underlying HIV-opioids interaction, in humans, we will use advanced brain imaging technologies and quantitative sensory testing (QST). Specifically, integrated [11C]PBR28 Positron Emission Tomography / Magnetic Resonance (PET/MR) and high field (7T) proton magnetic resonance spectroscopy (1H MRS) will be used to evaluate brain levels of glial markers (18kDa translocator protein, TSPO, and myo-inositol, mI), neuronal / structural integrity markers (N-acetyl- aspartate, NAA and gray matter volume) as well as excitatory and inhibitory neurotransmission markers (glutamate and gamma-aminobutyric acid, GABA). QST techniques will assess pain threshold, suprathreshold sensitivity and temporal summation. Four cohorts will be enrolled in this trial: 1) HIV-positive patients without neuropathic pain, 2) HIV-positive patients with neuropathic pain not on opioid therapy, 3) HIV-positive patients with neuropathic pain on opioid therapy and 4) healthy, pain-free HIV- volunteers. Elucidating the mechanisms mediating the HIV-opioid interaction will have important practical implications for pain management, and toward the development of tailored interventions focused on glial modulation and neurotransmitter signaling.