Molecular and Cellular Neurobiology Program
Cellular and Molecular Biology and Physiology Branch
Division of Basic and Translational Sciences
Objective: The goal of this initiative is to stimulate basic research on the role of glial cells in orofacial pain disorders and in particular, studies on the interactions between glial cells and neurons that lead to pathological pain states. This initiative will encourage multidisciplinary studies on 1) the influence of activated glial cells (astrocytes and microglia) on nociceptive neuron function in experimental pain models; 2) the mechanisms by which stimulation of primary afferent nociceptors (neurons) lead to activation of spinal cord, brain, and peripheral glial cells; 3) the identification of glial cell proteins and signaling pathways important in maintaining chronic pain states; 4) the neuronal proteins and signaling systems regulated by activated glial cells; and 5) the role of activated microglia as antigen presenting cells influencing systemic immune cell interactions with the CNS. The knowledge gained from integrated approaches like those above will lead to new advances in drug discovery for chronic pain disorders.
Background: Chronic orofacial pain affects an estimated 10% of the adult population and is a major reason for physician visits. Chronic pain also is a common symptom of temporomandibular joint disorders which affect about 10 million Americans. This pain can outlive initial injuries or damage and is thought to be a disorder in its own right. Analgesic drugs useful for treating acute pain are not always successful for chronic pain and patients rarely report the complete elimination of pain from drug treatment alone. The reasons for this lack of success in pain treatment include an incomplete understanding of the mechanisms of chronic pain induction and maintenance, a complex etiology of pain involving both neuropathic and neuroinflammatory processes, the targeting of most analgesic therapies to neurons, and the limited types of analgesic drugs currently available.
The current focus of pain research has been on neuronal function and on nerve networks that convey nociceptive information from the periphery to the central nervous system and then feed back to peripheral tissues. Even studies on inflammatory pain mostly focus on the responses of the neurons and neuronal-specific mechanisms of hypersensitivity and chronicity. These approaches have been extremely useful in delineating the neuroanatomical basis of nociception, the molecular mechanisms of neuron-neuron communication in pain pathways, and neuron-specific mechanisms inducing hypersensitive pain states. Few studies have addressed the role that non-neuronal cells play in the initiation and maintenance of chronic pain and specifically, the mechanisms by which activated glial cells influence the function of neurons and neuronal networks in the pain pathway(s). Nor has the anti-inflammatory and regenerative/repair capability of glial cells been explored in great depth.
There are three types of glial cells in the central nervous system: microglia, oligodendrocytes, and astrocytes. The microglia are generally quiescent under normal conditions. Oligodendrocytes and astrocytes are found in close apposition to neurons. The oligodendrocytes produce myelin, which ensheathes neuronal axons. The astrocytes form networks with themselves, are closely associated with neurons and blood vessels, and their activity is generally thought to mirror the metabolic activity of neurons. Recent research has demonstrated that glial cells play an important role in neuronal development and function. They also have both reparative and degenerative properties in the adult nervous system. They can influence synaptic strength and the formation and elimination of synapses. They are able to influence broad networks of neuronal activity, but propagate their signaling several orders of magnitude slower than neurons.
Glial cells contain neurotransmitters and express receptors and transporters for neurotransmitters and are thus poised to both receive signals from neurons, and release neurotransmitters to synaptic and non-synaptic sites on neurons. Microglia and astrocytes become activated in models of both neuropathic and inflammatory nerve injury. The microglia seem to be activated initially and then activate astrocytes. Both can release pro-inflammatory cytokines that influence a variety of neuronal cell functions. Activated microglia also act as antigen presenting cells and thus may influence immune cell infiltration into the CNS. It is clear that microglia and astrocytes are important in maintaining chronic pain states, since metabolic inhibitors specific to glial cells will reverse chronic pain in experimental models. On the other hand, microglia have salutary effects in the nervous system, protecting and aiding the repair and regeneration of injured neurons. They secrete neurotrophic factors like NGF and BDNF and produce antioxidant proteins.
Treatment of intractable pain currently is less than satisfactory. One reason for this is that we do not yet fully understand the molecular mechanisms underlying the development and maintenance of chronic pathological pain states. There are few studies exploring the role of glial cells in hyperalgesia and allodynia. However, there is considerable ongoing research on the role of glial cells and neuro-immune interactions in traumatic brain injury, autoimmune disorders such as multiple sclerosis, and AIDS-related dementia. There is an increasing interest in studies of the interactions of glial cells and neuronal cells in normal conditions and disease states but there is a distinct lack of research on how these interactions influence pain processes. Methodology and tools exist to study glial cells and to selectively modify the function of these cells. This Initiative is likely to attract new researchers to the NIDCR who would apply novel approaches to study molecular mechanisms of orofacial pain. Data derived from studies on the role of glial cells in normal neuronal function can provide the basis for additional work exploring the interactions between neurons and glia that lead to pathological conditions. Emphasis of research in this area may lead to new therapeutic approaches and targets for analgesia.
Current Portfolio Overview: The current NIDCR portfolio includes grants that are studying inflammatory pain in the orofacial region; yet these grants are focused on neuronal changes: the neuronal networks, the ion channels and neurotransmitter receptors, and neuron-specific plasticity. Although several NIDCR grantees are examining the influence of cytokines on neuronal function in experimental pain, none are studying the interactions of neurons and glial cells that regulate cytokine production and activity.
Collaborative Activities: The objectives and content of this Concept Clearance are consistent with the interests of the Institutes and Centers participating in the NIH Pain Consortium.
Funding Mechanisms: This Initiative will utilize the R01 and R21 mechanisms.