Itch is a prevalent and debilitating side effect that follows neuraxial (intrathecal and epidural) morphine administration and has limited the therapeutic potential of opioids for pain. Nevertheless, the cellular basis of morphine-induced itch remains unclear. Morphine acts at the mu opioid receptor (MOR) to inhibit neuronal activity. Thus, it follows that morphine can cause itch through inhibition of inhibitory neurons that gate itch. I seek to test the hypothesis that neuraxial morphine causes itch through disinhibition. I propose to determine which subtype(s) of spinal interneurons is/are responsible for morphine-induced itch. There are five distinct subtypes of inhibitory neurons in the spinal cord dorsal horn that can be distinguished using distinct neurochemical markers and targeted with specific Cre alleles. Of these, two have previously been implicated in the inhibition of itch and are, therefore, ideal candidates. I propose to identify which of these five populations is responsible for morphine-induced itch using a combination of behavioral, anatomical, and physiological approaches. My proposal comprises the following aims:
Aim 1 : Determine whether the expression of MOR in spinal inhibitory neurons is required for morphine-induced itch.
Aim 2 : Determine which cell types express MOR.
Aim 3 : Determine which cell types are inhibited by morphine. Together, these experiments could reveal the cellular basis for morphine-induced itch for the first time. This information is critically important because a better understanding of how morphine causes itch in the spinal cord can lead to improved treatments for pain that do not cause itch. Thus, this work integrates closely with my clinical interest in anesthesiology. In this proposal, I outline a combination of rigorous mentored research training, longitudinal clinical experiences, coursework, and professional and leadership development activities. The intellectual, technical, and professional skills refined during this fellowship training period will be instrumental in my development as an aspiring physician scientist in the clinical field of academic anesthesiology.
Itch is a common and serious adverse effect associated with neuraxial opioid-based pain treatment. The mechanism by which morphine causes itch remains unclear. In this proposal, I will investigate the cellular basis for morphine-induced itch using a combination of behavioral, molecular, and electrophysiological approaches.