Orofacial pain is one of the most prevalent and debilitating conditions arising from the structures innervated by the trigeminal system (head, face, masticatory musculature, temporomandibular joint and associated structures). The most significant complications from dental procedures such as surgical interventions and root canal treatments are iatrogenic trigeminal nerve injuries, which can result in trigeminal neuropathic pain causing considerable functional and psychological disability. The current management of trigeminal neuropathic pain is inadequate. For a major number of patients, the therapeutic options available do not deliver successful pain control, or intolerable side effects arise resulting in their discontinued use and poor quality of life. Trigeminal neuropathic pain (TNP) is the result of sensitization in the peripheral nervous system (PNS) and in areas within the central nervous system (CNS) related to pain processing, but we do not understand completely the mechanisms of this sensitization and unfortunately this has limited the creation of new therapeutic options. Activation of A3AR (adenosine A3 receptor) has been shown to be a safe therapeutic approach producing persistent pain relief in neuropathic pain models. In addition, our preliminary data support peroxynitrite (PN), a free radical that is a powerful antioxidant and nitrating agent involved in neuropathic pain mechanisms, to be involved also in orofacial pain. Together, this suggests that A3AR activation may represent a novel therapeutic approach in TNP, via a downstream mechanism that involves preventing the production of PN. Therefore research efforts will be focused on activating A3AR in a rat model of trigeminal nerve injury that resembles the TNP observed in humans, with the use of a highly selective drug (A3AR agonist) that has been shown to induce strong pain relief in diverse rodent models of neuropathic pain. In addition, we will determine the involvement of PN in trigeminal neuropathic pain, and establishing whether the A3AR agonist blocks PN formation. To focus experimental objectives, we hypothesize that: ?Highly selective A3AR agonists are protective against TNP by decreasing PN production?. To test this hypothesis we will use molecular biological techniques to first determine the expression of A3AR along the PNS and central areas within the brain that are involved in processing trigeminal pain information. Second, we will investigate whether activation of A3AR relieves persistent pain in the rat model of trigeminal nerve injury, using behavioral nociceptive sensory thresholds. Third, using immunohistochemistry we will investigate whether TNP induces PN formation in the same areas in the PNS and CNS regions were A3AR is located and if activation of A3AR blocks PN formation. Testing this hypothesis is highly significant because it will provide the foundation for a new translational effort for the use of drugs that activate the A3AR for the management of TNP, supporting for the first time, A3AR activation as a protective function against TNP, while providing insight into an initial mechanistic understanding of sensitization after trigeminal injury involving PN pathways.

Public Health Relevance

The most significant complications from dental procedures such as surgical interventions and root canal treatments are iatrogenic trigeminal nerve injuries, which can result in trigeminal neuropathic pain. Trigeminal neuropathic pain (TNP) is a devastating and maladaptive response that can arise after sensitization from trigeminal nerve injury in the orofacial region, causing considerable functional and psychological disability, of which the current management is inadequate. The successful completion of the proposed studies has the potential to lay the foundation to change the current strategies for the management of TNP, promoting activation of the A3AR (adenosine A3 receptor) as a target and protective mechanism against TNP, and a novel molecular mechanism, through the production of peroxynitrite - a nitroxidative species- , in its pathophysiology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Small Research Grants (R03)
Project #
7R03DE026253-02
Application #
9653635
Study Section
NIDR Special Grants Review Committee (DSR)
Program Officer
Vallejo, Yolanda F
Project Start
2017-06-01
Project End
2019-05-31
Budget Start
2017-10-11
Budget End
2018-05-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Other Basic Sciences
Type
Schools of Dentistry/Oral Hygn
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201