Endogenous and Exogenous Opioids in Pain

Corder, Gregory; Castro, Daniel C.; Bruchas, Michael R.; Scherrer, Grégory

doi:10.1146/annurev-neuro-080317-061522

Cited by 288 publications

(289 citation statements)

References 177 publications

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“…Mu and delta opioid receptors (MOP, DOP) are GPCRs widely distributed within the somatosensory nervous system, including ascending and descending pain pathways (Corder, Castro, Bruchas, & Scherrer, ; Gavériaux‐Ruff & Kieffer, ). Both receptors are activated by endogenous and exogenous opioids and control nociception under physiological conditions (Corder et al, ). MOP control sensitivity to heat (Matthes et al, ), whereas DOP participates in touch perception (Bardoni et al, ; Martin, Matifas, Maldonado, & Kieffer, ).…”

Section: Introductionmentioning

confidence: 99%

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Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

Martínez-Navarro

Cabañero

Wawrzczak-Bargieła

et al. 2020

British J Pharmacology

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Background and Purpose Mu and delta opioid receptors(MOP, DOP) contribution to the manifestations of pathological pain is not understood. We used genetic approaches to investigate the opioid mechanisms modulating neuropathic pain and its comorbid manifestations. Experimental Approach We generated conditional knockout mice with MOP or DOP deletion in sensoryNav1.8‐positive neurons (Nav1.8), in GABAergic forebrain neurons (DLX5/6) orconstitutively (CMV). Mutant mice and wild‐type littermates were subjected topartial sciatic nerve ligation (PSNL) or sham surgery and their nociception wascompared. Anxiety‐, depressivelike behaviour and cognitive performance were also measured. Opioid receptor mRNA expression, microgliosis and astrocytosis were assessed in the dorsalroot ganglia (DRG) and/or the spinal cord (SC). Key Results Constitutive CMV‐MOP knockouts after PSNL displayed reduced mechanical allodynia and enhanced heat hyperalgesia. This phenotype was accompanied by increased DOP expression in DRG and SC, and reduced microgliosis and astrocytosis in deep dorsal horn laminae. Conditional MOP knockouts and control mice developed similar hypersensitivity after PSNL, except for anenhanced heat hyperalgesia by DLX5/6‐MOP male mice. Neuropathic pain‐induced anxiety was aggravated in CMV‐MOP and DLX5/6‐MOP knockouts. Nerve‐injured CMV‐DOP mice showed increased mechanical allodynia, whereas Nav1.8‐DOP and DLX5/8‐DOP mice had partial nociceptive enhancement. CMV‐DOP and DLX5/6‐DOP mutants showed increased depressive‐like behaviour after PSNL. Conclusions and Implications MOP activity after nerve injury increased anxiety‐like responses involving forebrain GABAergic neurons and enhanced mechanical pain sensitivity along with repression of DOP expression and spinal cord gliosis. In contrast, DOP shows a protective function limiting nociceptive and affective manifestations of neuropathic pain.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

Martínez-Navarro

Cabañero

Wawrzczak-Bargieła

et al. 2020

British J Pharmacology

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“…The clinical utility of opioids as analgesics is due to activation of opioid receptors in the brain and spinal cord (1), but chronic exposure tends to diminish these effects and produce analgesic tolerance. Conversely, opioid abuse liability is related to activation of receptors in portions of the mesolimbic dopamine system, including the ventral tegmental area and nucleus accumbens (2).…”

Section: Introductionmentioning

confidence: 99%

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Lefevre

Pisansky

Toddes

et al. 2019

Preprint

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Background: Drug-evoked adaptations in the mesolimbic dopamine system drive opioid abuse and addiction, but these adaptations vary in magnitude and direction following different patterns of opioid exposure. Despite fundamental links between the pattern of drug exposure and abuse liability, few studies have systematically manipulated the pattern of opioid administration while measuring neurobiological and behavioral impact. Methods:In male and female mice, we first compared the behavioral consequences of chronic morphine exposure for one week, across multiple doses and with administration patterns that were either intermittent (daily injections) or continuous (osmotic minipump infusion). We then interrupted continuous morphine exposure with twice-daily naloxone injections, and used next-generation RNA sequencing to perform genome-wide transcriptional profiling in the nucleus accumbens and dorsal striatum.Results: Continuous morphine exposure caused tolerance to both the antinociceptive and psychomotoractivating effects of morphine. In contrast, both intermittent and interrupted morphine exposure caused longlasting psychomotor sensitization. The interruption of continuous morphine exposure exacerbated drug-evoked transcriptional changes in the nucleus accumbens and dorsal striatum, dramatically increasing the number of differentially expressed transcripts and engaging unique signaling pathways. Conclusions:These experiments indicate that opioid-evoked adaptations in brain function and behavior are critically dependent on the pattern of drug administration, and exacerbated by interruption of continuous exposure. Maintaining continuity of chronic opioid administration may therefore represent a strategy to minimize detrimental effects on brain reward circuits. This may in turn reduce the risk of progression from opioid use to abuse, promoting safer use of opioid-based treatments for clinical indications.

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“…The afferent nociceptive influx from peripheral tissues is regulated by descending neurons and opioid receptors participate in this system at multiple levels (Vanderah, 2010). As an example, KOP has been found to be present in spinal cord dorsal root ganglia (Attali & Vogel, 1989;Corder, Castro, Bruchas, & Scherrer, 2018;Ji et al, 1995) where it inhibits synaptic transmission between primary and secondary afferent neurons (Vanderah, 2010) in response to agonists released by descending neurons. Opioid peptides and their receptors also regulate monoaminergic systems and notably mesolimbic dopaminergic functions (Lutz & Kieffer, 2013).…”

mentioning

confidence: 99%

Structure and dynamics of dynorphin peptide and its receptor

et al. 2019

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Dynorphin is a neuropeptide involved in pain, addiction and mood regulation. It exerts its activity by binding to the kappa opioid receptor (KOP) which belongs to the large family of G-protein coupled receptors. The dynorphin peptide was discovered in 1975, while its receptor was cloned in 1993. This review will describe: a) the activities and physiological functions of dynorphin and its receptor, b) early structure-activity relationship studies performed before cloning of the receptor (mostly pharmacological and biophysical studies of peptide analogues), c) structureactivity relationship studies performed after cloning of the receptor via receptor mutagenesis and the development of recombinant receptor expression systems, d) structural biology of the opiate receptors culminating in X-ray structures of the four opioid receptors in their inactive state and structures of MOP and KOP receptors in their active state. X-ray and EM structures are combined with NMR data, which gives complementary insight into receptor and peptide dynamics.Molecular modelling greatly benefited from the availability of atomic resolution 3D structures of receptor-ligand complexes and an example of the strategy used to model a dynorphin-KOP receptor complex using NMR data will be described. These achievements have led to a better understanding of the complex dynamics of KOP receptor activation and to the development of new ligands and drugs.

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Endogenous and Exogenous Opioids in Pain

Cited by 288 publications

References 177 publications

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

Mu and delta opioid receptors play opposite nociceptive and behavioural roles on nerve‐injured mice

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

Structure and dynamics of dynorphin peptide and its receptor

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