Featured Publications

An amygdalar neural ensemble that encodes the unpleasantness of pain      Corder et al.  Science . 2019                   +    Supplemental Materials    Pain is an unpleasant experience. How the brain’s affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.

An amygdalar neural ensemble that encodes the unpleasantness of pain

Corder et al. Science. 2019

+ Supplemental Materials

Pain is an unpleasant experience. How the brain’s affective neural circuits attribute this aversive quality to nociceptive information remains unknown. By means of time-lapse in vivo calcium imaging and neural activity manipulation in freely behaving mice encountering noxious stimuli, we identified a distinct neural ensemble in the basolateral amygdala that encodes the negative affective valence of pain. Silencing this nociceptive ensemble alleviated pain affective-motivational behaviors without altering the detection of noxious stimuli, withdrawal reflexes, anxiety, or reward. Following peripheral nerve injury, innocuous stimuli activated this nociceptive ensemble to drive dysfunctional perceptual changes associated with neuropathic pain, including pain aversion to light touch (allodynia). These results identify the amygdalar representations of noxious stimuli that are functionally required for the negative affective qualities of acute and chronic pain perception.

Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia      Corder et al. Nature Medicine 2017 (cover)    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.

Loss of μ opioid receptor signaling in nociceptors, but not microglia, abrogates morphine tolerance without disrupting analgesia

Corder et al. Nature Medicine 2017 (cover)

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.


Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence      Corder et al. Science. 2013 (cover)    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 (MORCA) 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, MORCA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MORCA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.

Constitutive μ-Opioid Receptor Activity Leads to Long-Term Endogenous Analgesia and Dependence

Corder et al. Science. 2013 (cover)

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 (MORCA) 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, MORCA initiates both analgesic signaling and a compensatory opponent process that generates endogenous opioid dependence. Tonic MORCA suppression of withdrawal hyperalgesia may prevent the transition from acute to chronic pain.


 
Structure-based discovery of opioid analgesics with reduced side effects      Manglik et al. Nature. 2016    Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.

Structure-based discovery of opioid analgesics with reduced side effects

Manglik et al. Nature. 2016

Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids—which include fatal respiratory depression—are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21—a potent Gi activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.


Endogenous and exogenous opioids in pain     Corder, Castro, Bruchas, Scherrer. Annual Review of Neuroscience. July 2018    Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein–coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system.We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.

Endogenous and exogenous opioids in pain

Corder, Castro, Bruchas, Scherrer. Annual Review of Neuroscience. July 2018

Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein–coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system.We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.


Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits      Wang et al. Neuron. 2018 (cover)    Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur  in vivo remains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.

Functional Divergence of Delta and Mu Opioid Receptor Organization in CNS Pain Circuits

Wang et al. Neuron. 2018 (cover)

Cellular interactions between delta and mu opioid receptors (DORs and MORs), including heteromerization, are thought to regulate opioid analgesia. However, the identity of the nociceptive neurons in which such interactions could occur in vivoremains elusive. Here we show that DOR-MOR co-expression is limited to small populations of excitatory interneurons and projection neurons in the spinal cord dorsal horn and unexpectedly predominates in ventral horn motor circuits. Similarly, DOR-MOR co-expression is rare in parabrachial, amygdalar, and cortical brain regions processing nociceptive information. We further demonstrate that in the discrete DOR-MOR co-expressing nociceptive neurons, the two receptors internalize and function independently. Finally, conditional knockout experiments revealed that DORs selectively regulate mechanical pain by controlling the excitability of somatostatin-positive dorsal horn interneurons. Collectively, our results illuminate the functional organization of DORs and MORs in CNS pain circuits and reappraise the importance of DOR-MOR cellular interactions for developing novel opioid analgesics.

Peer-reviewed publications

* denotes equal contributions

1.      Corder, G*, Ahanonu, B*, Grewe, B, Wang, D, Schnitzer, MJ, Scherrer, G. An amygdalar neural ensemble that encodes the unpleasantness of pain. Science. 2019 Jan; Vol. 363, Issue 6424, pp. 276-281. DOI: 10.1126/science.aap8586

2.      Corder, G*, Tawfik, VL*, Wang, D*, Sypek, ES*, Low, SA, Dickinson, JR, Sotoudeh, C, Clark, JD, Barres, B, Bohlen, C Scherrer, G. Loss of μ-opioid receptor signaling in nociceptors, and not spinal microglia, abrogates morphine tolerance without disrupting analgesia. Nature Medicine. 2017 Feb; 23(2):164-173. doi: 10.1038/nm.4262.

3.      Wang, D, Tawfik, VL, Corder, G, Low, SA, Basbaum, AI, Scherrer, G. Functional Divergence of Delta and Mu Opioid Receptors Organization in CNS Pain Circuits. Neuron. 2018 Apr 4;98(1):90-108.e5. doi: 10.1016/j.neuron.2018.03.002.

4.      Manglik, A*, Henry, L*, Aryal, DP*, McCorvy, JD, Dengler, D, Corder, G, Bernat, V, Huang, X, Sassano, MF, Giguere, PM, Levit, A, Lober, S, Hubner, H, Duan, D, Scherrer, G, Kobilka, BK, Gmeiner, P, Roth, BL, Shoichet, BK. Structure-based discovery of biased μ-opioid receptor analgesics with reduced side effects. Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112.

5.      Rowe R, Ellis G, Harrison J, Bachstetter A, Corder GF, Van Eldik L, Taylor BK, Marti F, Lifshitz J. Diffuse traumatic brain injury induces prolonged immune dysregulation and potentiates hyperalgesia following a peripheral immune challenge. Molecular Pain. 2016 May 13;12. doi: 10.1177/1744806916647055.

6.      Taylor, BK, Fu, W, Kuphal, KE, Stiller, CO, Winter, MK, Chen, W, Corder, GF, Urban, JH, McCarson, KE, Marvizon, JC. Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons. Neuroscience. 2014 Jan 3;256:178-94. doi: 10.1016/j.neuroscience.2013.10.054.

7.      Corder, G, Doolen, S, Winter, MW, Jutras, BL, He, Y, Hu, X, Wieskopf, JS, Mogil, JS, Storm, DR,  Wang, ZJ, McCarson, KE, Taylor, BK. Constitutive µ-opioid receptor activity leads to long-term endogenous analgesia and dependence. Science. 2013 Sep 20;341(6152):1394-9. doi: 10.1126/science.1239403.

8.      Solway, BM, Bose, S, Corder, G, Donahue, R, Taylor, BK. Tonic inhibition of chronic pain by Neuropeptide Y. PNAS, USA. 2011 Apr 26;108(17):7224-9. doi: 10.1073/pnas.1017719108.

9.      Corder, G, Siegel, A, Intondi, AB, Zhang, X, Zadina, JE, Taylor, BK. 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 Apr;11(4):388-98. doi: 10.1016/j.jpain.2009.09.008.

 

Reviews / Book Chapters

10.      Corder, G*, Castro, D*, Bruchas, M, Scherrer, G. Exogenous and endogenous opioids in pain. Annual Review of Neuroscience. Invited submissionpublication forthcoming in the ARN 2018 volume

11.   Taylor, BK and Corder, G.  Endogenous analgesia, dependence, and latent pain sensitization. Current Topics in Behavioral Neuroscience. 2014 Sep 17.  doi 10.1007/7854_2014_351. PMID: 25227929.

 

Dissertation

12. Corder, G. Injury Establishes Constitutive μ-Opioid Receptor Signaling Leading to Lasting Endogenous Analgesia and Dependence. University of Kentucky. 2013. http://uknowledge.uky.edu/physiology_etds/10/

 

Unpublished Work

13.      Corder, G*, Fu, W*, Donahue, R*, Winter, M, Pertin, M, Suter, M, Wiley, R, Hokfelt, T, Urban, J, Doolen, S, DeCosterd, I, McCarson, K, Taylor, B.K. Facilitation of neuropathic pain by the NPY Y1 receptor subpopulation of excitatory interneurons in the dorsal horn. (in preparation)