Recent surveys indicate that approximately 26 - 27 million individuals in the US suffer from moderate to severe chronic pain. A key pathophysiology of chronic pain is neurogenic inflammation, which is primarily elicited by activation of unmyelinated sensory neurons through noxious stimuli and the subsequent release of neuropeptides such as calcitonin gene-related peptide (CGRP) and substance P (SP) from the peripheral endings of these nociceptive neurons. Neurogenic inflammation has been implicated in the pathophysiology of various human diseases or syndromes with uncertain etiology, such as migraines, arthritis and complex regional pain syndrome. Animal studies suggest that released CGRP acting at its receptors may be critical in the etiology of neurogenic dural vasodilation, thought to be a critical link in the generation of migraine and other neurovascular pain. Recent clinical trials with a CGRP antagonist provide substantive support for this theory. Currently, the established selective CGRP receptor antagonist is the C-terminal fragment of the human a-CGRP (hCGRP8-37). Since hCGRP8-37 is not a small molecule, the delivery of this large peptide to neurogenic inflammatory sites represents a great challenge. We propose to use a microneedle-based technology to transdermally infuse hCGRP8-37 into an inflamed site of skin area of rats without the use of a standard needle and syringe. Unlike other microneedles, our microneedles are made of biocompatible water-dissolving """"""""generally recognized as safe"""""""" (GRAS) materials and impregnated with the biomolecule to be delivered, in this case hCGRP8-37. The microneedles penetrate the skin and dissolve in the interstitial fluid while delivering the biomolecule. Thus, we will take advantage of this novel drug delivery technology and the in-depth pain research expertise from our collaborator, Dr. David Yeomans at Stanford University, to develop and test an innovative anti-CGRP microneedle patch.
Our Specific Aims are to - 1. Fabricate the dissolvable microneedle patch incorporating hCGRP8-37 and determine the antagonist release kinetics from the microneedles using acutely prepared rat cadaver skin in vitro. 2. Evaluate the effectiveness of the anti-CGRP microneedle patch in a neurogenic inflammatory pain model in rats using pain behavior assessments and oedema measurements. The objective of this Phase I project is to test the hypothesis that the dissolvable microneedle patch can deliver the CGRP receptor antagonist in a slow sustained diffusion manner into neurogenically inflamed sites, and consequently block hyperalgesia and oedema in the capsaicin neurogenic inflammation rat model. Our ultimate goal is to develop safe, effective and convenient microneedle patches to block peripheral CGRP receptor-mediated nociceptive and inflammatory responses that occur under pathologic, neurogenic pain conditions. Recent surveys indicate that approximately 26 - 27 million individuals in the US suffer from moderate to severe pain. One of major causes of pain is neurogenic inflammation which is associated with chronic pain syndromes such as migraines, arthritis and complex regional pain syndrome. Animal studies suggest that the pain is related to CGRP release, which can be prevented by a sustained supply of anti-CGRP to the inflammation sites. We propose the development of an innovative anti-CGRP patch for the treatment of neurogenic inflammatory pain. ? ? ?
| Xie, Xinmin Simon (2015) The neuronal circuit between nociceptin/orphanin FQ and hypocretins/orexins coordinately modulates stress-induced analgesia and anxiety-related behavior. Vitam Horm 97:295-321 |
