The Role of PDGFR-β Signaling in Opioid Tolerance
The Gutstein Lab discovered that the clinically used platelet-derived growth factor receptor (PDGFR-β) antagonist imatinib (Gleevec®) completely blocks and reverses morphine tolerance (Wang et al, 2012). This finding lead to the groundbreaking discovery that the analgesia-producing and tolerance-inducing properties of morphine can be totally dissociated and that PDGFR-β signaling is a primary and highly selective substrate of morphine tolerance. We also discovered that increases in PDGFR-β signaling caused by neuropathic changes renders neuropathic pain insensitive to opioids (Donica et al, 2013).
Based on those observations, we now aim to determine the molecular, cellular, and neuroanatomical mechanisms underlying this phenomenon. Part of our work focuses on determining whether PDGFR-β signaling also mediates tolerance to the main mu-opioid agonists used in the clinic by addressing the question of incomplete cross-tolerance. Further investigations will also determine whether this growth factor receptor could also mediate the other serious adverse side-effects of opioids.
The Role of RTK Signaling in Opioid Tolerance
Recently, the Gutstein Lab discovered that the clinically used epidermal growth factor receptor (EGFR; ErbB1) antagonist gefitinib (Iressa) also completely reverses morphine tolerance with very strong and long lasting beneficial effects on morphine analgesia. Thus, we are performing studies to define the mechanisms by which ErbB receptor signaling mediates opioid tolerance; determine the effects of opioid tolerance on ErbB signaling; and define the specific cellular subtypes expressing ErbB receptors in the pain processing pathways in order to begin to define the network structure that underlies opioid tolerance. These studies should dramatically improve our understanding of the molecular mechanisms underlying opioid tolerance and may lead to a completely new approach for the treatment of chronic pain.
The Role of hedgehog signaling in Tolerance and Sensitization
In our previous work, we made the completely unexpected discovery that Hedgehog (Hh) signaling mediated both thermal allodynia and thermal hyperalgesia in the fly (Babcock et al, 2011). Surprisingly, inhibition of Hh signaling using specific Smoothened (Smo) inhibitors or inhibitors of the specific signaling cascade in rodents did not cause analgesia in models of thermal hyperalgesia or mechanical allodynia; rather, it blocked the development of tolerance to the analgesic effects of morphine in each of these conditions.
The mechanism by which Hh signaling reverses tolerance is completely unknown. With a multidisciplinary approach, we aim to elucidate the involvement of Hh in tolerance and sensitization.