“…In addition, although the systemic injection of fentanyl causes profound analgesia in rats, it also exerts adverse effects on ventilatory parameters, the alveolar–arterial (A-a) gradient (index of alveolar gas exchange), and arterial blood–gas chemistry ( Henderson et al, 2014 ; Baby et al, 2021 ; Jenkins et al, 2021 ; Getsy et al, 2022a ; Getsy et al, 2022b ; Seckler et al, 2022 ; Marchette et al, 2023 ). The roles of μ-, δ-, and κ-opioid receptors ( Trescott et al, 2008 ; Valentino and Volkow, 2018 ), cell-signaling/molecular mechanisms ( Al-Hasani and Bruchas, 2011 ; Shang and Filizola, 2015 ), and multiple sites of action of opioids ( May et al, 1989 ; Lalley, 2003 ; Vadivelu et al, 2011 ; Henderson et al, 2013 ; 2014 ; Baby et al, 2018 ; Birdsong and Williams, 2020 ; Rossi and Bodnar, 2021 ) have been extensively studied. With regard to in vivo pharmacological approaches, the acute systemic administration of centrally acting opioid receptor antagonists such as naloxone and peripherally restricted antagonists such as methyl-naloxone (naloxone methiodide, NLXmi) has provided important evidence pertaining to the central and peripheral sites involved in mediating the actions of opioids ( Lewanowitsch and Irvine, 2002 ; 2003 ; Lewanowitsch et al, 2006 ; Leppert, 2010 ; Yamamoto and Sugimoto, 2010 ; Mori et al, 2013 ; Henderson et al, 2014 ; Belltall et al, 2022 ).…”