title: Opposite effects of mu and delta opioid receptor agonists on excitatory propagation induced in rat somatosensory and insular cortices by dental pulp stimulation.
abstract: The insular cortex (IC) contributes to nociceptive information processing. IC neurons express opioid receptors, including the mu (MOR), kappa (KOR), and delta (DOR) subtypes. Opioidergic agonists suppress excitatory synaptic transmission in the cerebral cortex. In addition, morphine injection into the IC reduces responses to noxious thermal stimuli. However, the mechanisms of the opioid-dependent modulation of cortical excitation at the macroscopic level, which bridge the cellular and behavioral findings, have remained unknown. The present in vivo optical imaging study aimed to examine the effects of the agonists of each subtype on cortical excitatory propagation in the IC and the neighboring cortices, the primary (S1) and secondary somatosensory (S2) areas. To assess the opioidergic effects on the cortical circuits, we applied electrical stimulation to the maxillary 1st molar pulp, which induced excitation in the ventral part of S1 and the S2/insular oral region (IOR). The initial excitatory response was observed 10-14ms after stimulation, and then excitation propagated concentrically. DAMGO (10-100μM), an MOR agonist, suppressed the amplitude of cortical excitation and shrank the maximum excitation areas in S1 and S2/IOR. In contrast, 10-100μM DPDPE, a DOR agonist, increased the amplitude of excitation and expanded the area of maximum excitation. U50488 (10-100μM), a KOR agonist, had little effect on cortical excitation. These results suggest that MOR-induced suppression of excitatory propagation in the IC is an underlying mechanism of the powerful analgesic effects of MOR agonists. In contrast, DOR may play a minor role in suppressing acute pain.
authors.affiliation: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Department of Anesthesiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Yokota
authors.affiliation: Department of Anesthesiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Koyanagi
authors.affiliation: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Department of Pediatric Dentistry, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Orthodontics, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Horinuki
authors.affiliation: Department of Anesthesiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Oi
authors.affiliation: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; Division of Oral and Craniomaxillofacial Research, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan; RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. Electronic address: kobayashi.masayuki@nihon-u.ac.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology*; D000071080:Cortical Excitability / Q000187:drug effects*; D003782:Dental Pulp; D004558:Electric Stimulation; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000008:administration & dosage; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000008:administration & dosage; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000502:physiology*; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D000701:Analgesics, Opioid; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-
keywords: Insular cortex; Nociception; Opioid receptors; Optical imaging; Pain