The primary focus of the Gold lab is peripheral mechanisms of pain. The major themes currently pursued are derived from a growing body of evidence indicating that the underlying mechanisms of persistent pain vary as a function of a number of factors, including type of injury, site of injury, and sex and age of the injured organism. Within this context, ongoing projects are focused on: 1) migraine and post-traumatic brain injury-induced headache, 2) trigeminal neuralgia, 3) temporomandibular joint disorder, 4) chemotherapeutic-induced peripheral neuropathy, 5) functional and inflammatory visceral pain disorders, 6) persistent inflammatory pain, and 7) the factors that influence the management of post-operative pain. Many of the specific questions addressed in pre-clinical models and human tissue are derived from clinical observations, where ongoing collaborations with clinicians enable a comparative analysis of pre-clinical models and pain patients.
MECHANISMS OF MIGRAINE
The clinical observations driving this line of investigation include the follow: 1) migraine is far more prevalent in women than men, 2) there are a high density of typically resident (mast cells and macrophages) and recruited (T-cells and B-cells) immune cells in the dura, 3) immune cells are both responsive to mediators released during stress and gonadal hormones, 4) the dura is heavily innervated by sympathetic post-ganglionic neurons, 5) stress has been shown to result in delayed sensitization of nociceptive afferents, and 6) stress is the most prevalent trigger for a migraine attack.
We have expanded this study to include the analysis of human dura tissue. Furthermore, given evidence of similarities between the signs and symptoms of migraine with those of post traumatic brain injury-induced (PTBI) headache, we have also expanded this project to include the study of mechanisms contributing to the manifestation of PTBI headache.
TRIGEMINAL NEURALGIA (TN)
The clinical observations driving this line of investigation include the following: 1) Classical TN involves pain attacks triggered by low threshold mechanical stimulation of cutaneous trigger points, 2) TN is more common in women than men, but in contrast to other pain syndromes that are more prevalent in women, is more common later in life, 3) TN in a subset of patients is well managed with the drug carbamazepine, and 4) this same drug has failed in trials of the management of other types of neuropathic pain.
TEMPOROMANDULAR JOINT DISORDER (TMJD)
TMJD is another pain disorder that is highly disabling that is far more prevalent in men than in women. While a number of different mechanisms are likely to contribute to this highly heterogeneous pain syndrome, we have focused on changes that occur in the joint that occur in response to altered loading, such as occurs in association with parafunctional habbits such as teeth clenching and grinding, as well as in association with trauma to the teeth or jaw. With evidence that there is degeneration of the joint lining, we are testing hypotheses regarding mechanisms that contribute to both the initiation and maintenance of the pain associated with TMJD.
MECHANISMS OF CHEMOTHERAPEUTIC-INDUCED PERIPHERAL NEUROPATHY (CIPN)
The primary dose-limiting side effect associated with the use of antineoplastic chemotherapeutic agents is the development of peripheral neuropathy. Because this neuropathy is also the major cause for early termination of treatment and can persist long after its cessation, identification of mechanisms underlying the neuropathy may not only suggest a way of providing pain relief for a significant number of cancer patients, but may enable more effective use of these compounds in the treatment of cancer. CIPN presents with numbness and tingling that may ultimately progress to debilitating pain in the glabrous skin of the hands and feet. Because the prevailing hypotheses do not account for these unique clinical features, we are pursuing an alternative hypothesis that we have recently expanded to account for the persistence of a variety of other persistent cognitive and emotional symptoms in cancer survivors that significant impact their quality of life.
FUNCTIONAL AND INFLAMMATORY VISCERAL PAIN DISORDERS
The “functional” pain disorders such as fibromyalgia and irritable bowel syndrome (IBS) are called functional pain disorders because of the presence of pain in the absence of clear sign of pathology in the periphery that could serve as the cause of the pain. The result is an ongoing debate in the field as to whether functional pain disorders are due to less obvious changes in the periphery or whether they reflect changes in the central nervous system. Based on a number of convergent lines of evidence, we have hypothesized that IBS, is due, at least in part, to the loss of peripheral GABA mediated inhibition of colonic afferents. As a corollary to this line of investigation, we are exploring changes in resident immune cells as a contributor to the change in GABA regulation. Visceral hypersensitivity associated overt inflammation is studied for comparison.
MECHANSISMS OF PERSISTENT INFLAMMATORY PAIN
This study arose from the observation that in contrast to afferents innervating several visceral structures in addition to the masseter muscle, persistent inflammation-induced sensitization of cutaneous afferents was not associated with a decrease in voltage-gated K+ current. Rather, sensitization of these afferents appears to reflect, at least in part, a decrease in Ca2+ dependent K+ current. This observation lead to a series of studies designed to identify the basis for these changes with a particular focus on the regulation of intracellular Ca2+. Results of this analysis revealed that the regulation of intracellular Ca2+ is disrupted in the presence of inflammation such that the depolarization-evoked increases in intracellular Ca2+ are larger and decay more slowly. Ongoing studies are therefore focused on the identification of mechanisms underlying these changes in Ca2+ regulation as well as the impact of these changes in inflammation-induced pain, changes in gene expression, and transmitter release
FACTORS THAT INFLUENCE THE MANAGEMENT OF POSTOPERATIVE PAIN
This study arose from the clinical observation that there are subpopulations of patients that appear to be less sensitive to the actions of local anesthetics. Given that regional anesthesia is growing in use for the management of pain both in the operating room and post-operatively, combined with evidence that the acute pain management can influence the development of chronic pain, factors that decrease local anesthetic potency may have significant consequences. Working between patient populations and pre-clinical models, we have identified a number of factors that are associated with a decrease in local anesthetic potency. Ongoing studies are designed to identify the mechanisms responsible for these changes.
THE STUDY OF HUMAN DORSAL ROOT GANGLION (DRG) NEURONS
We have learned a tremendous amount about nociceptive processing from the study of pre-clinical models in general and rodents in particular. However, it is now very clear that the biophysical and pharmacological properties or membrane bound proteins such as receptors and ion channels are influenced by the context in which these proteins reside. As a results, these properties may be influenced by expression system and species differences. To facilitate comparison of results generated in preclinical models and expression systems, we have developed protocols to study human DRG neurons in vitro. This model system should not only serve as an essential step for the screening of putative therapeutic compounds prior to the initiation of clinical trials, but used to validate key observations arising from the study of pre-clinical models.