The μ-opioid system is arguably one of the molecular mechanisms most involved in pain regulation, and it is the main target for the action of most exogenous opioids. Unfortunately, there is limited in vivo information available on the μ-opioid brain system in chronic pain patients and how they directly respond to pain, treatment and addiction. Although magnetic resonance techniques have provided insights into some brain mechanisms of migraine and pain in humans, many questions regarding their chronification and treatments still are unanswered. For instance, recent advances in neuroimaging and neuromodulation have provided important information, including the molecular mechanisms in the brain that are affected during the course of the patients’ suffering in vivo and how these opioid mechanisms can be modulated safely for therapeutic and research purposes. This presentation will focus on the most recent studies from the Headache & Orofacial Pain Effort (H.O.P.E.) laboratory at the University of Michigan School of Dentistry using positron emission tomography (PET) with a selective μ-opioid receptor (μOR) radiotracer in vivo. It will provide novel evidence that there are different endogenous opioid patterns in the brains of migraine, TMD and orofacial pain patients during pain/attack, allodynia and treatment, that are also affected by the patient’s clinical pain profile, including frequency, severity, as well as their genotype.