Tolerance to non‐opioid analgesics in PAG involves unresponsiveness of medullary pain‐modulating neurons in male rats
Abstract
Opiate analgesia can be hampered by a reduction in pharmacological effectiveness (tolerance), and this crucially depends on the periaqueductal gray matter (PAG). Non-opioids like metamizol (dipyrone) or aspirin also induce PAG-dependent analgesia and tolerance, but the neuronal bases of this tolerance are unknown. Metamizol is a pyrazolon derivative and cyclooxygenase inhibitor with widespread use as an analgesic in Europe and Latin America. Metamizol was microinjected into the PAG of awake male rats, and antinociception was assessed by the tail flick (TF) and hot plate (HP) tests. Microinjection twice daily for 2.5 days caused tolerance to metamizol. The rats were then anesthetized and recordings from pain-facilitating on-cells and pain-inhibiting off-cells of the rostral ventromedial medulla (RVM) were performed. PAG microinjection of morphine or metamizol depresses on-cells, activates off-cells and thus inhibits nociception, including TF and HP. In metamizol-tolerant rats, however, PAG microinjection of metamizol failed to affect on- or off-cells, and this is interpreted as the reason for tolerance. In metamizol-tolerant rats morphine microinjection into PAG also failed to affect RVM neurons or nociception (cross-tolerance). In naïve, non-tolerant rats the antinociceptive effect of PAG-microinjected metamizol or morphine was blocked when CTOP, a mu-opioid antagonist, was previously microinjected into the same PAG site. These results emphasize a close relationship between o…
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At the same time that cardiac sympathetic tone is increased, vagal cardiac parasympathetic tone is reduced.
“At the same time that cardiac sympathetic tone is increased, vagal cardiac parasympathetic tone is reduced.”
From Fear and the Defense Cascade (2015) · cites this paper as [51]
The reduction in vagal cardiac parasympathetic tone is mediated primarily by efferent vagal fibers that originate from the nucleus ambiguous and fire in synchrony with the respiratory cycle.
“According to current neurophysiological models,3,51 this process is mediated primarily by the efferent vagal fibers that originate from the nucleus ambiguous and that fire in synchrony with the respiratory cycle (respiratory-related cardiac vagal efferents) (see Supplemental Text Box 2, http://links.lww.com/HRP/A9).”
From Fear and the Defense Cascade (2015) · cites this paper as [51]
The integrated freeze response includes an opioid-mediated analgesia, which is itself mediated by the PAG and the rostral ventromedial medulla pain circuit.
“The integrated freeze response includes an opioid-mediated analgesia,28,29 which is itself mediated by the PAG and the rostral ventromedial medulla pain circuit.71”
From Fear and the Defense Cascade (2015) · cites this paper as [71]
The antinociceptive response elicited during tonic immobility is opioid mediated and involves activation of the PAG and the rostral ventromedial medulla pain circuit.
“The antinociceptive response elicited during tonic immobility is opioid mediated103,104 and involves activation of the PAG and the rostral ventromedial medulla pain circuit.71”
From Fear and the Defense Cascade (2015) · cites this paper as [71]
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- Authors
- Tortorici, V., Aponte, Y., Acevedo, H., Nogueira, L., & Vanegas, H.
- Affiliations
- Instituto Venezolano de Investigaciones Científicas (VE)
- Venue
- European Journal of Neuroscience
- Publisher
- Wiley
- Published
- 2009-03
- Volume
- 29
- Issue
- 6
- Pages
- 1188-1196
- ISSN
- 0953-816X (ISSN-L)
- 1460-9568
- OpenAlex
- W2158280608
- Cited by
- 23
- References
- 48
- Citations by year
- 2025: 1 · 2019: 2 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- analgesic tolerance, periaqueductal gray, dipyrone, non-opioid analgesics, morphine, cross-tolerance, rostral ventromedial medulla, mu-opioid receptor, CTOP, opioid analgesia, antinociception
- MeSH terms
- Action Potentials, Animals, Aspirin, Dipyrone, Drug Tolerance, Male, Medulla Oblongata, Morphine, Narcotics, Neurons, Pain, Pain Measurement, Periaqueductal Gray, Reaction Time, Somatostatin, Analgesics, Non-Narcotic, Rats
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