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Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons.
Neuroscience. 2014 Jun 20; 271:149-59.N

Abstract

Chronic pain reflects not only sensitization of the ascending nociceptive pathways, but also changes in descending modulation. The rostral ventromedial medulla (RVM) is a key structure in a well-studied descending pathway, and contains two classes of modulatory neurons, the ON-cells and the OFF-cells. Disinhibition of OFF-cells depresses nociception; increased ON-cell activity facilitates nociception. Multiple lines of evidence show that sensitization of ON-cells contributes to chronic pain, and reversing or blocking this sensitization is of interest as a treatment of persistent pain. Neuropeptide Y (NPY) acting via the Y1 receptor has been shown to attenuate hypersensitivity in nerve-injured animals without affecting normal nociception when microinjected into the RVM, but the neural basis for this effect was unknown. We hypothesized that behavioral anti-hyperalgesia was due to selective inhibition of ON-cells by NPY at the Y1 receptor. To explore the possibility of Y1 selectivity on ON-cells, we stained for the NPY-Y1 receptor in the RVM, and found it broadly expressed on both serotonergic and non-serotonergic neurons. In subsequent behavioral experiments, NPY microinjected into the RVM in lightly anesthetized animals reversed signs of mechanical hyperalgesia following either nerve injury or chronic hindpaw inflammation. Unexpectedly, rather than decreasing ON-cell activity, NPY increased spontaneous activity of both ON- and OFF-cells without altering noxious-evoked changes in firing. Based on these results, we conclude that the anti-hyperalgesic effects of NPY in the RVM are not explained by selective inhibition of ON-cells, but rather by increased spontaneous activity of OFF-cells. Although ON-cells undoubtedly facilitate nociception and contribute to hypersensitivity, the present results highlight the importance of parallel OFF-cell-mediated descending inhibition in limiting the expression of chronic pain.

Authors+Show Affiliations

Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States. Electronic address: clearyd@ohsu.edu.Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States.Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States; Department of Anesthesia, Cairo University Hospital, Cairo, Egypt.Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States; Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24792711

Citation

Cleary, D R., et al. "Neuropeptide Y in the Rostral Ventromedial Medulla Reverses Inflammatory and Nerve Injury Hyperalgesia in Rats Via Non-selective Excitation of Local Neurons." Neuroscience, vol. 271, 2014, pp. 149-59.
Cleary DR, Roeder Z, Elkhatib R, et al. Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons. Neuroscience. 2014;271:149-59.
Cleary, D. R., Roeder, Z., Elkhatib, R., & Heinricher, M. M. (2014). Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons. Neuroscience, 271, 149-59. https://doi.org/10.1016/j.neuroscience.2014.04.035
Cleary DR, et al. Neuropeptide Y in the Rostral Ventromedial Medulla Reverses Inflammatory and Nerve Injury Hyperalgesia in Rats Via Non-selective Excitation of Local Neurons. Neuroscience. 2014 Jun 20;271:149-59. PubMed PMID: 24792711.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons. AU - Cleary,D R, AU - Roeder,Z, AU - Elkhatib,R, AU - Heinricher,M M, Y1 - 2014/04/30/ PY - 2014/03/10/received PY - 2014/04/18/revised PY - 2014/04/21/accepted PY - 2014/5/6/entrez PY - 2014/5/6/pubmed PY - 2015/1/15/medline KW - NPY KW - OFF-cells KW - ON-cells KW - descending pain modulation KW - nociception KW - raphe magnus SP - 149 EP - 59 JF - Neuroscience JO - Neuroscience VL - 271 N2 - Chronic pain reflects not only sensitization of the ascending nociceptive pathways, but also changes in descending modulation. The rostral ventromedial medulla (RVM) is a key structure in a well-studied descending pathway, and contains two classes of modulatory neurons, the ON-cells and the OFF-cells. Disinhibition of OFF-cells depresses nociception; increased ON-cell activity facilitates nociception. Multiple lines of evidence show that sensitization of ON-cells contributes to chronic pain, and reversing or blocking this sensitization is of interest as a treatment of persistent pain. Neuropeptide Y (NPY) acting via the Y1 receptor has been shown to attenuate hypersensitivity in nerve-injured animals without affecting normal nociception when microinjected into the RVM, but the neural basis for this effect was unknown. We hypothesized that behavioral anti-hyperalgesia was due to selective inhibition of ON-cells by NPY at the Y1 receptor. To explore the possibility of Y1 selectivity on ON-cells, we stained for the NPY-Y1 receptor in the RVM, and found it broadly expressed on both serotonergic and non-serotonergic neurons. In subsequent behavioral experiments, NPY microinjected into the RVM in lightly anesthetized animals reversed signs of mechanical hyperalgesia following either nerve injury or chronic hindpaw inflammation. Unexpectedly, rather than decreasing ON-cell activity, NPY increased spontaneous activity of both ON- and OFF-cells without altering noxious-evoked changes in firing. Based on these results, we conclude that the anti-hyperalgesic effects of NPY in the RVM are not explained by selective inhibition of ON-cells, but rather by increased spontaneous activity of OFF-cells. Although ON-cells undoubtedly facilitate nociception and contribute to hypersensitivity, the present results highlight the importance of parallel OFF-cell-mediated descending inhibition in limiting the expression of chronic pain. SN - 1873-7544 UR - https://www.unboundmedicine.com/medline/citation/24792711/Neuropeptide_Y_in_the_rostral_ventromedial_medulla_reverses_inflammatory_and_nerve_injury_hyperalgesia_in_rats_via_non_selective_excitation_of_local_neurons_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(14)00338-8 DB - PRIME DP - Unbound Medicine ER -