Honors & Awards
NIH Pathway to Independence Award - K99/R00, National Institute on Drug Abuse (NIDA)
NRSA F32 Fellowship, National Institute on Drug Abuse (NIDA)
T32 Fellowship - Pain and Substance Use Disorders, National Institute on Drug Abuse (NIDA)
SNI Interdisciplinary Scholar Award - Honorable Mention, Stanford Neurosciences Institute
Dean's Fellowship, Stanford School of Medicine
NRSA F31 Fellowship, National Institute on Drug Abuse (NIDA)
Doctor of Philosophy, University of Kentucky (2013)
Bachelor of Science, Tulane University of Louisiana (2007)
- Endogenous and Exogenous Opioids in Pain Annual Review of Neuroscience 2018
Loss of mu opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia
2017; 23 (2): 164-173
Opioid pain medications have detrimental side effects including analgesic tolerance and opioid-induced hyperalgesia (OIH). Tolerance and OIH counteract opioid analgesia and drive dose escalation. The cell types and receptors on which opioids act to initiate these maladaptive processes remain disputed, which has prevented the development of therapies to maximize and sustain opioid analgesic efficacy. We found that μ opioid receptors (MORs) expressed by primary afferent nociceptors initiate tolerance and OIH development. RNA sequencing and histological analysis revealed that MORs are expressed by nociceptors, but not by spinal microglia. Deletion of MORs specifically in nociceptors eliminated morphine tolerance, OIH and pronociceptive synaptic long-term potentiation without altering antinociception. Furthermore, we found that co-administration of methylnaltrexone bromide, a peripherally restricted MOR antagonist, was sufficient to abrogate morphine tolerance and OIH without diminishing antinociception in perioperative and chronic pain models. Collectively, our data support the idea that opioid agonists can be combined with peripheral MOR antagonists to limit analgesic tolerance and OIH.
View details for DOI 10.1038/nm.4262
View details for Web of Science ID 000393729000008
View details for PubMedID 28092666
View details for PubMedCentralID PMC5296291
- Structure-based discovery of opioid analgesics with reduced side effects NATURE 2016; 537 (7619): 185-?
Constitutive mu-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence
2013; 341 (6152): 1394-1399
Opioid receptor antagonists increase hyperalgesia in humans and animals, which indicates that endogenous activation of opioid receptors provides relief from acute pain; however, the mechanisms of long-term opioid inhibition of pathological pain have remained elusive. We found that tissue injury produced μ-opioid receptor (MOR) constitutive activity (MOR(CA)) that repressed spinal nociceptive signaling for months. Pharmacological blockade during the posthyperalgesia state with MOR inverse agonists reinstated central pain sensitization and precipitated hallmarks of opioid withdrawal (including adenosine 3',5'-monophosphate overshoot and hyperalgesia) that required N-methyl-D-aspartate receptor activation of adenylyl cyclase type 1. Thus, MOR(CA) initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MOR(CA) suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.
View details for DOI 10.1126/science.1239403
View details for Web of Science ID 000324597200047
View details for PubMedID 24052307
- Functional divergence of delta and mu opioid receptor organization in CNS pain circuits Neuron 2018
Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge.
Nociceptive and neuropathic pain occurs as part of the disease process after traumatic brain injury (TBI) in humans. Central and peripheral inflammation, a major secondary injury process initiated by the traumatic brain injury event, has been implicated in the potentiation of peripheral nociceptive pain. We hypothesized that the inflammatory response to diffuse traumatic brain injury potentiates persistent pain through prolonged immune dysregulation.To test this, adult, male C57BL/6 mice were subjected to midline fluid percussion brain injury or to sham procedure. One cohort of mice was analyzed for inflammation-related cytokine levels in cortical biopsies and serum along an acute time course. In a second cohort, peripheral inflammation was induced seven days after surgery/injury with an intraplantar injection of carrageenan. This was followed by measurement of mechanical hyperalgesia, glial fibrillary acidic protein and Iba1 immunohistochemical analysis of neuroinflammation in the brain, and flow cytometric analysis of T-cell differentiation in mucosal lymph. Traumatic brain injury increased interleukin-6 and chemokine ligand 1 levels in the cortex and serum that peaked within 1-9 h and then resolved. Intraplantar carrageenan produced mechanical hyperalgesia that was potentiated by traumatic brain injury. Further, mucosal T cells from brain-injured mice showed a distinct deficiency in the ability to differentiate into inflammation-suppressing regulatory T cells (Tregs).We conclude that traumatic brain injury increased the inflammatory pain associated with cutaneous inflammation by contributing to systemic immune dysregulation. Regulatory T cells are immune suppressors and failure of T cells to differentiate into regulatory T cells leads to unregulated cytokine production which may contribute to the potentiation of peripheral pain through the excitation of peripheral sensory neurons. In addition, regulatory T cells are identified as a potential target for therapeutic rebalancing of peripheral immune homeostasis to improve functional outcome and decrease the incidence of peripheral inflammatory pain following traumatic brain injury.
View details for DOI 10.1177/1744806916647055
View details for PubMedID 27178244
INFLAMMATION ENHANCES Y1 RECEPTOR SIGNALING, NEUROPEPTIDE Y-MEDIATED INHIBITION OF HYPERALGESIA, AND SUBSTANCE P RELEASE FROM PRIMARY AFFERENT NEURONS
2014; 256: 178-194
Neuropeptide Y (NPY) is present in the superficial laminae of the dorsal horn and inhibits spinal nociceptive processing, but the mechanisms underlying its anti-hyperalgesic actions are unclear. We hypothesized that NPY acts at neuropeptide Y1 receptors in the dorsal horn to decrease nociception by inhibiting substance P (SP) release, and that these effects are enhanced by inflammation. To evaluate SP release, we used microdialysis and neurokinin 1 receptor (NK1R) internalization in rat. NPY decreased capsaicin-evoked SP-like immunoreactivity in the microdialysate of the dorsal horn. NPY also decreased non-noxious stimulus (paw brush)-evoked NK1R internalization (as well as mechanical hyperalgesia and mechanical and cold allodynia) after intraplantar injection of carrageenan. Similarly, in rat spinal cord slices with dorsal root attached, [Leu(31), Pro(34)]-NPY inhibited dorsal root stimulus-evoked NK1R internalization. In rat dorsal root ganglion neurons, Y1 receptors colocalized extensively with calcitonin gene-related peptide (CGRP). In dorsal horn neurons, Y1 receptors were extensively expressed and this may have masked the detection of terminal co-localization with CGRP or SP. To determine whether the pain inhibitory actions of Y1 receptors are enhanced by inflammation, we administered [Leu(31), Pro(34)]-NPY after intraplantar injection of complete Freund's adjuvant (CFA) in rat. We found that [Leu(31), Pro(34)]-NPY reduced paw clamp-induced NK1R internalization in CFA rats but not uninjured controls. To determine the contribution of increased Y1 receptor-G protein coupling, we measured [(35)S]GTPγS binding simulated by [Leu(31), Pro(34)]-NPY in mouse dorsal horn. CFA inflammation increased the affinity of Y1 receptor G-protein coupling. We conclude that Y1 receptors contribute to the anti-hyperalgesic effects of NPY by mediating the inhibition of SP release, and that Y1 receptor signaling in the dorsal horn is enhanced during inflammatory nociception.
View details for DOI 10.1016/j.neuroscience.2013.10.054
View details for Web of Science ID 000330485500018
View details for PubMedID 24184981
Endogenous Analgesia, Dependence, and Latent Pain Sensitization.
Current topics in behavioral neurosciences
Endogenous activation of µ-opioidOpioid receptors (MORs) provides relief from acute painPain . Recent studies have established that tissue inflammation produces latent painPain sensitization (LS) that is masked by spinal MOR signaling for months, even after complete recovery from injury and re-establishment of normal painPain thresholds. Disruption with MOR inverse agonists reinstates painPain and precipitates cellular, somatic, and aversive signs of physical withdrawal; this phenomenon requires N-methyl-D-aspartate receptor N-methyl-D-aspartate receptor -mediated activation of calcium-sensitive adenylyl cyclaseAdenylyl cyclase type 1 (AC1). In this review, we present a new conceptual model of the transition from acute to chronic painPain , based on the delicate balance between LS and endogenous analgesiaAnalgesia that develops after painful tissue injury. First, injury activates painPain pathways. Second, the spinal cord establishes MOR constitutive activityConstitutive activity (MORCA) as it attempts to control painPain . Third, over time, the body becomes dependentDependent on MORCA, which paradoxically sensitizes painPain pathways. StressStress or injury escalates opposing inhibitory and excitatory influences on nociceptive processing as a pathological consequence of increased endogenous opioidOpioid tone. PainPain begets MORCA begets pain vulnerability in a vicious cycle. The final result is a silent insidious state characterized by the escalation of two opposing excitatory and inhibitory influences on painPain transmission: LS mediated by AC1 (which maintains the accelerator) and painPain inhibition mediated by MORCA (which maintains the brake). This raises the prospect that opposing homeostatic interactions between MORCA analgesiaAnalgesia and latent NMDAR-ACNMDAR-AC 1-mediated painPain sensitization creates a lasting vulnerability to develop chronic painPain . Thus, chronic painPain syndromes may result from a failure in constitutiveConstitutive signaling of spinal MORs and a loss of endogenous analgesicAnalgesic control. An overarching long-term therapeutic goal of future research is to alleviate chronic painPain by either (a) facilitating endogenous opioidOpioid analgesiaAnalgesia , thus restricting LS within a state of remission, or (b) extinguishing LS altogether.
View details for DOI 10.1007/7854_2014_351
View details for PubMedID 25227929
Tonic inhibition of chronic pain by neuropeptide Y
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2011; 108 (17): 7224-7229
Dramatically up-regulated in the dorsal horn of the mammalian spinal cord following inflammation or nerve injury, neuropeptide Y (NPY) is poised to regulate the transmission of sensory signals. We found that doxycycline-induced conditional in vivo (Npy(tet/tet)) knockdown of NPY produced rapid, reversible, and repeatable increases in the intensity and duration of tactile and thermal hypersensitivity. Remarkably, when allowed to resolve for several weeks, behavioral hypersensitivity could be dramatically reinstated with NPY knockdown or intrathecal administration of Y1 or Y2 receptor antagonists. In addition, Y2 antagonism increased dorsal horn expression of Fos and phosphorylated form of extracellular signal-related kinase. Taken together, these data establish spinal NPY receptor systems as an endogenous braking mechanism that exerts a tonic, long-lasting, broad-spectrum inhibitory control of spinal nociceptive transmission, thus impeding the transition from acute to chronic pain. NPY and its receptors appear to be part of a mechanism whereby mammals naturally recover from the hyperalgesia associated with inflammation or nerve injury.
View details for DOI 10.1073/pnas.1017719108
View details for Web of Science ID 000289888500100
View details for PubMedID 21482764
A Novel Method to Quantify Histochemical Changes Throughout the Mediolateral Axis of the Substantia Gelatinosa After Spared Nerve Injury: Characterization with TRPV1 and Substance P
JOURNAL OF PAIN
2010; 11 (4): 388-398
Nerve injury dramatically increases or decreases protein expression in the spinal cord dorsal horn. Whether the spatial distribution of these changes is restricted to the central innervation territories of injured nerves or could spread to adjacent territories in the dorsal horn is not understood. To address this question, we developed a simple computer software-assisted method to precisely distinguish and efficiently quantify immunohistochemical staining patterns across the mediolateral axis of the dorsal horn 2 weeks after transection of either the tibial and common peroneal nerves (thus sparing the sural branch, spared nerve injury, [SNI]), the tibial nerve, or the common peroneal and sural nerves. Using thiamine monophosphatase (TMP) histochemistry, we determined that central terminals of the tibial, common peroneal, sural, and posterior cutaneous nerves occupy the medial 35%, medial-central 20%, central-lateral 20%, and lateral 25% of the substantia gelatinosa, respectively. We then used these calculations to show that SNI reduced the expression of SP and TRPV1 immunoreactivity within the tibial and peroneal innervation territories in the L4 dorsal horn, without changing expression in the uninjured, sural sector. We conclude that SNI-induced loss of SP and TRPV1 in central terminals of dorsal horn is restricted to injured fibers. Our new method enables direct comparison of injured and uninjured terminals in the dorsal horn so as to better understand their relative contributions to mechanisms of chronic pain.A simple computer software-assisted algorithm was developed to precisely distinguish and efficiently quantify immunohistochemical staining patterns across the mediolateral axis of the dorsal horn after distal sciatic-branch transection. This method will facilitate a better understanding of the relative contribution of injured and uninjured terminals to mechanisms of chronic pain.
View details for DOI 10.1016/j.jpain.2009.09.008
View details for Web of Science ID 000276658700011
View details for PubMedID 20350706