Trigeminal neuropathic pain (TNP) is a major medical problem. Injury or surgery in the trigeminal area induces debilitating persistent neuropathic pain. Since TNP is often resistant to current pharmacotherapy, there is a pressing need to develop more efficacious treatments for TNP with fewer side effects. Neuropathic pain is maintained by a myriad of mechanisms involving multiple molecules and neural circuits across peripheral and central nervous systems. A recent study found that sensitized nociceptors likely maintain pain in approximately one third of neuropathic pain patients. Thus, identifying and determining mechanisms of dominant peripheral contributors to pain is critical for developing selective treatment for this subset of chronic pain patients. Lack of understanding of detailed mechanisms underlying the role of nociceptors in neuropathic pain poses a significant hurdle to improving nociceptor-targeted pain management in chronic pain sufferers. TRPV1 is a nociceptor- enriched receptor for capsaicin. Topical capsaicin invariably induces burning pain. Paradoxically, such nociception is often followed by prolonged analgesia attenuating pre-existing persistent pain. Topical capsaicin has been approved by the FDA for treatment of post-herpetic neuralgia, and provides months-long relief. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Despite clear therapeutic effects of capsaicin, the involvement of TRPV1 and TRPV1+ nociceptors in neuropathic pain is controversial. We recently reported evidence in a mouse model that TRPV1 and TRPV1+ nociceptors contributed to mechanical hyperalgesia and allodynia following neuropathy in the trigeminal area. The mechanical hyperalgesia and allodynia usually observed in mice subjected to chronic constriction injury of the infraorbital nerve (ION-CCI) was prevented by systemic pretreatment with resiniferatoxin, an ultrapotent TRPV1 agonist which desensitizes TRPV1+ afferents. We also found that local pharmacological inhibition of TRPV1 at the central terminals of primary afferents was sufficient to attenuate mechanical hyperalgesia and allodynia. Our objectives here are to determine the roles of TRPV1 and TRPV1+ nociceptors in TNP and to elucidate mechanisms of capsaicin-induced analgesia for TNP. Our central hypothesis is that plastic changes in trigeminal TRPV1+ nociceptors caused by nerve injury and vanilloid compounds, respectively, are critical for the maintenance and treatment of chronic TNP. To test this, we will determine the effects of ablation or inhibition of TRPV1+ afferents on mechanical hyperalgesia or spontaneous pain in mice with ION-CCI (Aim 1), define the major molecular pathway determining both capsaicin-induced ablation of peripheral terminals of TRPV1+ afferents and capsaicin-induced analgesia (Aim 2) and dissect the contribution of distinct genetically defined subpopulations of TRPV1+ afferents to TNP through conditional TRPV1 knockdown and elucidation of neurochemical and functional plasticity (aim 3). This study may identify neurobiological mechanisms underlying the contributions of TRPV1+ nociceptors to TNP, which may define TRPV1 as an attractive target for this condition, and reveal mechanisms of capsaicin therapy, a centuries-old enigma.
The goal of this project is to elucidate how pain receptor TRPV1 contributes to chronic pain under pathological conditions. This is an important step for the development of novel therapeutics targeting the pain receptor TRPV1 and nerves expressing TRPV1 more specifically with fewer side effects for suppressing pathological pain.
