Glutamate-mediated excitatory postsynaptic potentials (EPSPs) augment synaptic plasticity and amplify centrally mediated pain sensitivity (central sensitization). Upregulation of brain-derived neurotrophic factor (BDNF) during central sensitization may potentiate long-term neuroplastic alterations in pain circuitry, persistent secondary hyperalgesia, and sensitized responses to normally non-painful stimuli. A physiologic stress response and cortisol secretion during an acute pain experience may facilitate central sensitization by increasing glutamate, upregulating N-methyl-D-aspartate receptors, and prolonging calcium uptake. Cortisol-induced upregulation of BDNF may facilitate long-term potentiation of centrally mediated pain sensitivity and consolidate a fear-based memory of pain that is sensitized and readily recruited, manifesting as chronic pain. Interestingly, the impact of cortisol on central sensitization, as measured by functional magnetic resonance imaging (fMRI) of the brain, has not been explored. Therefore, the current study utilizes fMRI to clarify the relationship between cortisol and temporal summation (TS), a validated measure of central sensitization whereby repeated static suprathreshold heat pulses are perceived as increasing in intensity. We hypothesize that salivary cortisol concentration will predict increases in centrally mediated pain sensitivity during suprathreshold pulses of heat (TS) as compared to rest. During an acute episode of laboratory-induced musculoskeletal back pain, 10 subjects underwent fMRI during 4 trains of 6 static suprathreshold heat pulses separated by 20s rest periods (TS). Using multiple regression in SPM12, we examined salivary cortisol as a predictor of hemodynamic response (brain activity) during TS as compared to rest. Elevated cortisol was associated with increased responsiveness in the insula (x=34,y=-22,z=21;k=1799;p<.001FWE-corr), claustrum (x=-26,y=13,z=21;k=516;p<.001FWE-corr), posterior cingulate (x=-22,y=-59,z=16;k=151;p=.05FWE-corr), and superior temporal gyrus (x=48,y=-50,z=14;k=133;p=.07FWE-corr). Given the role of cortisol in central sensitization and neuroplastic alterations in pain processing, minimizing stress and cortisol secretion during acute pain may attenuate central pain sensitivity and prevent the transition from acute to chronic pain. Funded by the NIH, NCAAM, AT006334. Glutamate-mediated excitatory postsynaptic potentials (EPSPs) augment synaptic plasticity and amplify centrally mediated pain sensitivity (central sensitization). Upregulation of brain-derived neurotrophic factor (BDNF) during central sensitization may potentiate long-term neuroplastic alterations in pain circuitry, persistent secondary hyperalgesia, and sensitized responses to normally non-painful stimuli. A physiologic stress response and cortisol secretion during an acute pain experience may facilitate central sensitization by increasing glutamate, upregulating N-methyl-D-aspartate receptors, and prolonging calcium uptake. Cortisol-induced upregulation of BDNF may facilitate long-term potentiation of centrally mediated pain sensitivity and consolidate a fear-based memory of pain that is sensitized and readily recruited, manifesting as chronic pain. Interestingly, the impact of cortisol on central sensitization, as measured by functional magnetic resonance imaging (fMRI) of the brain, has not been explored. Therefore, the current study utilizes fMRI to clarify the relationship between cortisol and temporal summation (TS), a validated measure of central sensitization whereby repeated static suprathreshold heat pulses are perceived as increasing in intensity. We hypothesize that salivary cortisol concentration will predict increases in centrally mediated pain sensitivity during suprathreshold pulses of heat (TS) as compared to rest. During an acute episode of laboratory-induced musculoskeletal back pain, 10 subjects underwent fMRI during 4 trains of 6 static suprathreshold heat pulses separated by 20s rest periods (TS). Using multiple regression in SPM12, we examined salivary cortisol as a predictor of hemodynamic response (brain activity) during TS as compared to rest. Elevated cortisol was associated with increased responsiveness in the insula (x=34,y=-22,z=21;k=1799;p<.001FWE-corr), claustrum (x=-26,y=13,z=21;k=516;p<.001FWE-corr), posterior cingulate (x=-22,y=-59,z=16;k=151;p=.05FWE-corr), and superior temporal gyrus (x=48,y=-50,z=14;k=133;p=.07FWE-corr). Given the role of cortisol in central sensitization and neuroplastic alterations in pain processing, minimizing stress and cortisol secretion during acute pain may attenuate central pain sensitivity and prevent the transition from acute to chronic pain. Funded by the NIH, NCAAM, AT006334.