Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak

Rossi, Grace C.; Bodnar, Richard J.

doi:10.1007/s10571-020-00961-9

Cited by 4 publications

(3 citation statements)

References 429 publications

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“…68 Therefore, the activation of postsynaptic MOR is likely to suppress the descending noradrenergic pain inhibition. The postsynaptic inhibitory effects of MOR on LC-spinal neurons are difficult to reconcile with the analgesic effects of morphine and other MOR agonists administered into the LC, 76,100,146 nevertheless a bidirectional role of opioids in the control of the descending noradrenergic modulation would not be surprising as it has also been reported for the A 7 noradrenergic cell group. 66 At the LC, although the presynaptic (disinhibition) mechanism might be predominant, the postsynaptic effects might contribute to the overall excitability of LC-spinal neurons, namely, in circumstances requiring the adaptation of LC excitability.…”

Section: Opioidergic Modulation Of Brainstem Descending Pain Circuitsmentioning

confidence: 99%

“…In addition, the modulation of these brainstem circuits involves the opioidergic modulation of upstream brain structures, such as the prefrontal and anterior cingulate cortex and the amygdala, with which the PAG is connected. 10,13,146,164 In the PAG, GABAergic interneurons are a critical site of action of opioids. Opioids act through postsynaptic MORs, directly inhibiting GABAergic interneurons at the PAG, or through presynaptic MORs to inhibit the release of GABA (g-aminobutyric acid) from nerve terminals.…”

Section: Opioidergic Modulation Of Brainstem Descending Pain Circuitsmentioning

confidence: 99%

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How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

Costa

Tavares

Martins

2023

Pain

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Brainstem areas involved in descending pain modulation are crucial for the analgesic actions of opioids. However, the role of opioids in these areas during tolerance, opioid-induced hyperalgesia (OIH), and in chronic pain settings remains underappreciated. We conducted a revision of the recent studies performed in the main brainstem areas devoted to descending pain modulation with a special focus on the medullary dorsal reticular nucleus (DRt), as a distinctive pain facilitatory area and a key player in the diffuse noxious inhibitory control paradigm. We show that maladaptive processes within the signaling of the µ-opioid receptor (MOR), which entail desensitization and a switch to excitatory signaling, occur in the brainstem, contributing to tolerance and OIH. In the context of chronic pain, the alterations found are complex and depend on the area and model of chronic pain. For example, the downregulation of MOR and δ-opioid receptor (DOR) in some areas, including the DRt, during neuropathic pain likely contributes to the inefficacy of opioids. However, the upregulation of MOR and DOR, at the rostral ventromedial medulla, in inflammatory pain models, suggests therapeutic avenues to explore. Mechanistically, the rationale for the diversity and complexity of alterations in the brainstem is likely provided by the alternative splicing of opioid receptors and the heteromerization of MOR. In conclusion, this review emphasizes how important it is to consider the effects of opioids at these circuits when using opioids for the treatment of chronic pain and for the development of safer and effective opioids.

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Section: Opioidergic Modulation Of Brainstem Descending Pain Circuitsmentioning

confidence: 99%

Section: Opioidergic Modulation Of Brainstem Descending Pain Circuitsmentioning

confidence: 99%

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

Costa

Tavares

Martins

2023

Pain

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“…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 ).…”

Section: Introductionmentioning

confidence: 99%

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing

Baby,

May,

Getsy

et al. 2024

Front. Pharmacol.

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Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75 μg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0 mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5 mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5 mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.

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Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak

et al. 2021

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Interactive Mechanisms of Supraspinal Sites of Opioid Analgesic Action: A Festschrift to Dr. Gavril W. Pasternak

Cited by 4 publications

References 429 publications

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

How do opioids control pain circuits in the brainstem during opioid-induced disorders and in chronic pain? Implications for the treatment of chronic pain

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing

Understanding Opioid Actions, Pain and Analgesia: A Tribute to Dr. Gavril Pasternak

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