Carl R. Potenzieri, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): The analgesic properties of cannabis have been noted for centuries. However, the use of cannabis to treat pain is limited due to its psychoactive properties and abuse liability. Therapeutic applications may still be possible through the selective activation of peripheral cannabinoid receptors. Cannabinoid 1 (CB1) receptors have been localized to primary afferent neurons and cutaneous nerve terminals. Also, previous studies using animal models of both acute and persistent pain, such as inflammation, have demonstrated that locally administered cannabinoid receptor agonists produce peripherally mediated antihyperalgesia. The extent to which cannabinoids alter responses of nociceptors in this peripherally mediated antihyperalgesia is not currently known. [unreadable] [unreadable] Using correlative behavioral and in vivo teased-fiber electrophysiological methods, the overall objective of this proposal is to determine the peripheral neural mechanisms by which cannabinoid decrease hyperalgesia. We hypothesize that during adjuvant-evoked inflammation, activation of peripheral CB1 receptors will decrease the evoked responses of cutaneous A6 and C nociceptors and attenuate hyperalgesia. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: [unreadable] These studies will provide insight into the peripheral mechanisms of cannabinoid-mediated analgesia. Results may have a direct impact on the future development of novel, peripherally acting medications to treat pain. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The symptoms and pathophysiology of allergic airway disease involve perturbations in the neural regulation of respiration. A subset of vagal sensory nerves in the airways, the unmyelinated C-fibers, relay information to central nervous system regarding inhaled substances that are potentially harmful or noxious. Activation of bronchopulmonary C-fibers results in the initiation of defensive reflexes such as urge to cough, dyspnea, and increased cholinergic output leading to mucus secretion and bronchoconstriction to aid in the clearance of harmful substances from the airways. During allergic inflammation in the airways, however, the activity of bronchopulmonary C-fibers becomes enhanced or sensitized which can result in the symptoms of allergic airway disease such the dry incessant cough, bronchospasm, mucus secretion, and dyspnea. The excitability of bronchopulmonary C-fibers is strongly influenced by inflammatory mediators;however, little is known about the mechanism underlying bronchopulmonary C-fiber sensitization during allergic inflammation. The overall aim of this proposal is to determine the role of an inflammatory mediator strongly upregulated during both allergic and viral airway disease, "regulated upon activation, normal T-cell expressed and secreted" (RANTES), also known as CC chemokine ligand-5 (CCL5), has on the excitability of bronchopulmonary C-fibers. Using gene expression and immunohistochemical studies, we will characterize the specific receptors for CCL5 found on lung-specific vagal sensory neurons. Using electrophysiological methods, we will determine the effect of CCL5 on the excitability of lung-specific vagal sensory neurons and their of peripheral nerve terminals. We hypothesize that receptors for CCL5 are found on bronchopulmonary C-fibers and activation of these receptors by CCL5 will both excite and sensitize the responses of bronchopulmonary C-fibers. The overall results from these studies will implicate CCL5, not only as a chemokine recruiting leukocytes during allergen and viral- induced airway inflammation, but also as key molecule in the recruitment of nervous system during airway inflammation through sensitization of vagal bronchopulmonary C-fiber activity. PUBLIC HEALTH RELEVANCE: These studies will provide novel insight into the pathophysiology of allergic and viral airway diseases. Results may have a direct impact on the future development of treatments for these complex, interrelated diseases.