Mu and kappa opioid receptors of the periaqueductal gray stimulate and inhibit thermogenesis, respectively, during psychological stress in rats


The periaqueductal gray matter (PAG) is rich in mu and kappa opioid receptors, and this system is involved in thermoregulation, analgesia, and defensive behaviors. No study approached the involvement of the PAG opioids in body temperature (Tb) regulation during psychological stress such as restraint. Because activation of mu and kappa receptors increases and reduces Tb, respectively, we tested the hypothesis that they exert excitatory and inhibitory modulation, respectively, of the restraint-induced fever in rats. To this end, Tb, heat loss index (HLI, inference for peripheral vasoconstriction/vasodilation), and oxygen consumption (inference for thermogenesis) were monitored in unanesthetized rats, restrained or unrestrained, before and after intra-PAG microinjection of the selective mu opioid receptor antagonist (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 cyclic, CTAP; 1 and 10 μg/100 nL) or the selective kappa opioid receptor antagonist (nor-binaltorphimine dihydrochloride, nor-BNI; 1 and 4 μg/100 nL) or saline (100 nL). CTAP and nor-BNI did not change the Tb or HLI of euthermic animals. During restraint, Tb increased (1.0 ± 0.1 °C) in all groups; however, this effect was lower in those animals treated with CTAP and higher in animals treated with nor-BNI. The HLI decreased during restraint and increased after animals were released, but this response was not affected by any treatment. Restraint stress increased oxygen consumption (35.9 ± 3.9% elevation), but this response was diminished by CTAP and overstimulated by nor-BNI. Confirming our hypothesis, the results indicate that the mu and kappa opioid receptors in the PAG of rats play a pyrogenic and antipyretic role, respectively, during fever induced by restraint by affecting the thermogenic but not the heat conservation effector.

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This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP undergraduate fellowship 2013/02813-9 to C.C.S.; grant 2015/04849-6 to K.C.B.) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES graduate fellowships to C.C.S. and V.M.). This study was part of the activities developed by C.C.S. for obtaining a master’s degree at the Joint Graduate Program in Physiological Sciences (PIPGCF) from UFSCar/UNESP. We thank Euclides Roberto Secato and Damares Perecim Roviero for their technical assistance.

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Cristina-Silva, C., Martins, V., Gargaglioni, L.H. et al. Mu and kappa opioid receptors of the periaqueductal gray stimulate and inhibit thermogenesis, respectively, during psychological stress in rats. Pflugers Arch - Eur J Physiol 469, 1151–1161 (2017).

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  • Body temperature
  • Heat loss index
  • Oxygen consumption
  • Opioid receptors
  • Nor-BNI
  • CTAP