The development of animal models of persistent pain has advanced our knowledge of the initiation of pain hypersensitivity due to sensitization of peripheral nociceptors and neurons in the medullary and spinal dorsal horns as well as other sites in the central nervous system (CNS). It is now commonly proposed that the initiation of this plasticity and resultant pain amplification is dependent upon activation of peripheral nociceptors. It is assumed that peripheral mechanisms are also responsible for the maintenance of the pain hypersensitivity, though the findings in this area are less compelling. Recent findings suggest that behavioral hyperalgesia following injury persists despite a reduction in peripheral neuronal activity suggesting that peripheral drive may be necessary but not sufficient for the maintenance of pain hypersensitivity after injury. The primary aim of this proposal is to study the mechanisms that underlie the maintenance of pain amplification after injury and to determine whether there are CNS mechanisms that participate in pain chronicity and how persistent pain emerges from the more acute stage after injury. Current animal models are not entirely adequate for the study of the chronicity and maintenance of pain hypersensitivity. We have developed two new models in the trigeminal system: a tendomyositis model of the masseter muscle and a neuropathic pain model of the infraorbital nerve. Both models exhibit long-term hyperalgesia/allodynia that is constant and lasts for months, and the inflammation due to the surgical procedure can be separated with the use of long-duration local anesthetics. Our major hypothesis is that tissue and nerve injury in the orofacial region can lead to the maintenance of secondary hyperalgesia that involves the activation CNS descending mechanisms and is less dependent on the peripheral drive associated with the injured target. The following Specific Aims will test these hypotheses using multidisciplinary approaches. #1: Test the hypothesis that the maintenance of long-term hyperalgesia after injury involves an attenuation of peripheral afferent drive and a transition to central mechanisms. #2: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory or a reduction of descending inhibitory inputs. #3: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory drive involving activation of trigeminal non-neural glial cells and their release of cytokines. #4: Test the hypothesis that the maintenance of long-term hyperalgesia is dependent upon an enhancement of descending facilitatory drive that involves shifts in the anionic reversal potential of trigeminal GABA-responsive neurons and a reduction in GABAA-induced inhibitory tone. #5: Test the hypothesis that the maintenance of long-term mechanical hyperalgesia is dependent upon rostral ventromedial medulla activation of a trigeminal brain stem interactive signaling cascade of 5-HT3, GABAA and NMDA receptors as well as glia and cytokines.
The major goal of the proposed research is to study the central nervous system mechanisms that account for the chronicity of persistent orofacial pain after tissue or nerve injury. Although it is now commonly proposed that the initiation of injury-induced neural plasticity and resultant pain amplification is dependent upon activation of peripheral nociceptors, it is unclear whether peripheral mechanisms are also responsible for the maintenance and chronicity of pain hypersensitivity and how persistent pain emerges from the more acute stage after injury. Our findings will lead to a transformative shift in the search for unique treatment approaches for persistent pain.
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