| Cutaneous injuries are common and painful. Additionally, incision size during surgery has been correlated with the degree of postoperative pain. Ineffective management of cutaneous pain can lead to complications including poor wound healing. Postoperative pain in human patients and in rodent models exhibits aspects of heat and mechanical hypersensitivity and spontaneous, non-evoked pain. In rodents, skin incisions induce mechanical and heat hypersensitivity similar to levels observed with deeper incisions that include damage to fascia and muscle. Therefore, cutaneous injury might drive a majority of the mechanical and heat hypersensitivity. Understanding the molecular mechanisms that underlie cutaneous injuryinduced pain may lead to topical treatment options for lacerations, puncture wounds, and postoperative pain.;Transient Receptor Potential (TRP) channels are non-specific cation channels expressed in the plasma membrane of sensory neurons that innervate peripheral tissues, including skin. The TRP Ankyrin 1 (TRPA1) and TRP Vanilloid 1 (TRPV1) channels mediate mechanical and heat hyperalgesia, respectively, in nerve injury and inflammatory models. Therefore, in my dissertation, I investigated the contribution of TRPA1 and TRPV1 in cutaneous injury-induced mechanical and heat hypersensitivity.;In my dissertation work which utilized genetic ablation and pharmacological inhibition, I show that TRPA1 does not mediate behavioral mechanical hypersensitivity with cutaneous injury. While conducting functional calcium imaging, I found that TRPA1 agonists predominantly excite a subpopulation of small-diameter dorsal root ganglia (DRG) neurons that are non-peptidergic (lack neuropeptides and bind isolectin-B4, IB4). When I conducted retrograde labeling of cutaneously-innervating afferents, most neurons excited by TRPA1 agonists were also IB4-binding. Among neurons with mixed peripheral tissue targets or among cutaneous neurons, TRPA1 is not functionally upregulated in DRG neurons after skin incision injury.;The TRPV1 channel is also high expressed in cutaneous afferent nociceptors. I explored the role of TRPV1 in cutaneous injury-induced heat hypersensitivity. The results indicate that TRPV1 mediates thermal hypersensitivity induced by skin incision in mouse. Further, TRPV1 function was increased in DRG neurons, specifically in IB4-binding neurons. Together, these findings suggest that enhanced TRPV1 function, particularly in IB4-binding neurons, underlies heat hypersensitivity following skin incision injury.;In conclusion, my dissertation work provides evidence that TRPA1 is functionally expressed in the IB4-binding subpopulation of sensory neurons, which are thought to feed into a pathway involved in emotional, affective aspects of pain. Although TRPA1 is largely expressed in cutaneous sensory neurons, TRPA1 does not mediate cutaneous injury-induced mechanical hypersensitivity. However, my dissertation work provides evidence for a role of TRPV1 in skin incision-induced pain. Ultimately, this work suggests that IB4-binding neurons may serve an important role in postoperative pain and that TRPV1 antagonists may be used to alleviate cutaneous injury pain. |
