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Mu-opioid and CB1 cannabinoid receptors of the dorsal periaqueductal gray interplay in the regulation of fear response, but not antinociception.
Pharmacol Biochem Behav. 2020 07; 194:172938.PB

Abstract

Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA.

Authors+Show Affiliations

Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H. dos Santos S/N, P.O. Box 19031, Curitiba, Paraná 81540-990, Brazil.Department of Pharmacology, School of Medicine, University of São Paulo, Av. Bandeirantes 3900, Ribeirão Preto, São Paulo 14049-900, Brazil.Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H. dos Santos S/N, P.O. Box 19031, Curitiba, Paraná 81540-990, Brazil; Institute of Neurosciences and Behavior and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirão Preto, SP 14040-900, Brazil.Department of Pharmacology, Biological Sciences Building, Federal University of Paraná, Rua Coronel H. dos Santos S/N, P.O. Box 19031, Curitiba, Paraná 81540-990, Brazil; Institute of Neurosciences and Behavior and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirão Preto, SP 14040-900, Brazil. Electronic address: janaina.zanoveli@ufpr.br.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32376258

Citation

Godoi, Manuella Machado, et al. "Mu-opioid and CB1 Cannabinoid Receptors of the Dorsal Periaqueductal Gray Interplay in the Regulation of Fear Response, but Not Antinociception." Pharmacology, Biochemistry, and Behavior, vol. 194, 2020, p. 172938.
Godoi MM, Junior HZ, da Cunha JM, et al. Mu-opioid and CB1 cannabinoid receptors of the dorsal periaqueductal gray interplay in the regulation of fear response, but not antinociception. Pharmacol Biochem Behav. 2020;194:172938.
Godoi, M. M., Junior, H. Z., da Cunha, J. M., & Zanoveli, J. M. (2020). Mu-opioid and CB1 cannabinoid receptors of the dorsal periaqueductal gray interplay in the regulation of fear response, but not antinociception. Pharmacology, Biochemistry, and Behavior, 194, 172938. https://doi.org/10.1016/j.pbb.2020.172938
Godoi MM, et al. Mu-opioid and CB1 Cannabinoid Receptors of the Dorsal Periaqueductal Gray Interplay in the Regulation of Fear Response, but Not Antinociception. Pharmacol Biochem Behav. 2020;194:172938. PubMed PMID: 32376258.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mu-opioid and CB1 cannabinoid receptors of the dorsal periaqueductal gray interplay in the regulation of fear response, but not antinociception. AU - Godoi,Manuella Machado, AU - Junior,Hélio Zangrossi, AU - da Cunha,Joice Maria, AU - Zanoveli,Janaina Menezes, Y1 - 2020/05/03/ PY - 2020/01/10/received PY - 2020/04/27/revised PY - 2020/04/28/accepted PY - 2020/5/8/pubmed PY - 2021/3/31/medline PY - 2020/5/8/entrez KW - Antinociception KW - Endocannabionoid KW - Fear KW - Freezing KW - Opioid KW - Periaqueductal gray SP - 172938 EP - 172938 JF - Pharmacology, biochemistry, and behavior JO - Pharmacol Biochem Behav VL - 194 N2 - Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA. SN - 1873-5177 UR - https://www.unboundmedicine.com/medline/citation/32376258/Mu_opioid_and_CB1_cannabinoid_receptors_of_the_dorsal_periaqueductal_gray_interplay_in_the_regulation_of_fear_response_but_not_antinociception_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091-3057(20)30019-8 DB - PRIME DP - Unbound Medicine ER -