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Ronald Dubner, PhD, DDS

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Organized Research Center on Persistent Pain | Contact Information |

Neural & Pain Sciences


Descending brain stem modulation of persistent pain and spinal cord neuronal plasticity

Hyperalgesia (increase in pain after injury) in animal models is linked to activation of descending modulatory circuits in the rostral ventromedial medulla (RVM) in the brain stem. These circuits originate in the forebrain and are responsible for the attentional, sensory, affective and cognitive components of the experience of pain. They include facilitatory and inhibitory mechanisms. Our studies examine how this descending circuitry is functionally linked to spinal and trigeminal mechanisms leading to behavioral hyperalgesia. We have examined the role of the spinal serotonin receptor 3 (5-HT3R), the GABAA receptor and NMDA receptors in inflammation- and nerve injury-induced hyperalgesia. The hyperalgesia is 5-HT3R-dependent at the spinal level. Activation of the 5-HT3R leads to neuron-to-microglia signaling via fractalkine, microglia to astrocyte signaling via IL-18 and its receptor, astrocyte to neuronal signaling by IL-1β, and enhances activation of NMDA receptors in the spinal dorsal horn. The SP-induced hyperalgesia is also GABAA and NMDA receptor-dependent and involves the functional interaction of spinal GABAA and NMDA receptors.  
Dr. Dubner

Neural and glial interactions

Recent studies indicate that the immune and glial cells interact with neurons in the development of pain hypersensitivity and mediate the transition from acute to persistent or chronic pain. In response to injury, resident immune cells are activated and blood-borne immune cells are recruited to the site of injury.  Immune cells not only contribute to immune protection, but also help to initiate peripheral nociceptive sensitization. Immune signals can reach the brain and spinal cord through afferent nerve input, circulating cytokines and immune cell trafficking, leading to an increased glial activity and central sensitization.  Through the synthesis and release of inflammatory mediators and interactions with neurotransmitters and their receptors, the immune cells, glial cells and neurons form an integrated network that not only coordinates immune responses but also modulates excitability of pain pathways. The immune system also plays a role in pain control through immune-derived analgesic and antiinflammatory/pro-resolution agents. Understanding the role of the immune system in pain processing and modulation reveals potential targets for analgesic drug development and offers new therapeutic opportunities for managing chronic pain.


Mechanisms of persistent orofacial pain

A major subgroup of patients with temporomandibular joint disorders (TMJD) have masticatory muscle hypersensitivity. To study myofacial temporomandibular pain, we have developed a model of myogenic orofacial pain that lasts for months. The model involves unilateral ligation of the tendon of the anterior superficial part of the rat masseter muscle (TASM), which is a distinct structure arising from the lateral surface of the maxilla. Nocifensive behavior of the rat was assessed by probing the skin site above the TASM with von Frey filaments. The response frequencies were determined and an EF50 value, defined as the force that produces a 50 percent response frequency, was derived.  We used EF50 values as a measure of mechanical sensitivity. Following TASM ligation, the EF50 of the injured side was significantly reduced for at least two months, suggesting long-lasting mechanical hyperalgesia/allodynia. The hyperalgesia was from the injured tendon since anesthetizing the tendon tissue, but not the cutaneous site, abolished hyperalgesia. Immunohistochemistry showed that Fos protein expression, as indicated by the number of Fos-positive cells in the superficial laminae of the medullary dorsal horn, was significantly increased in TASM-ligated rats. Western blot showed that NMDA receptor phosphorylation (P) and glial marker expression were enhanced after TASM ligation in the same region that showed Fos induction and lasted for at least 8 w. Thus, ligation injury of the TASM in rats led to long-lasting and constant mechanical hypersensitivity of myogenic origin, associated with somatotopically relevant neurochemical changes in the spinal trigeminal nucleus.