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Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats.
Eur J Neurosci. 2009 Mar; 29(6):1188-96.EJ

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 opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting.

Authors+Show Affiliations

Instituto Venezolano de Investigaciones Cientificas (IVIC), Caracas, Venezuela. victort@ivic.veNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

19302154

Citation

Tortorici, Victor, et al. "Tolerance to Non-opioid Analgesics in PAG Involves Unresponsiveness of Medullary Pain-modulating Neurons in Male Rats." The European Journal of Neuroscience, vol. 29, no. 6, 2009, pp. 1188-96.
Tortorici V, Aponte Y, Acevedo H, et al. Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats. Eur J Neurosci. 2009;29(6):1188-96.
Tortorici, V., Aponte, Y., Acevedo, H., Nogueira, L., & Vanegas, H. (2009). Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats. The European Journal of Neuroscience, 29(6), 1188-96. https://doi.org/10.1111/j.1460-9568.2009.06678.x
Tortorici V, et al. Tolerance to Non-opioid Analgesics in PAG Involves Unresponsiveness of Medullary Pain-modulating Neurons in Male Rats. Eur J Neurosci. 2009;29(6):1188-96. PubMed PMID: 19302154.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tolerance to non-opioid analgesics in PAG involves unresponsiveness of medullary pain-modulating neurons in male rats. AU - Tortorici,Victor, AU - Aponte,Yexica, AU - Acevedo,Humberto, AU - Nogueira,Lourdes, AU - Vanegas,Horacio, PY - 2009/3/24/entrez PY - 2009/3/24/pubmed PY - 2009/6/10/medline SP - 1188 EP - 96 JF - The European journal of neuroscience JO - Eur J Neurosci VL - 29 IS - 6 N2 - 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 opioid and non-opioid analgesic mechanisms in the PAG and show that, like morphine, tolerance to metamizol involves a failure of on- and off-cells to, respectively, disfacilitate and inhibit nociception. Cross-tolerance between non-opioid and opioid analgesics should be important in the clinical setting. SN - 1460-9568 UR - https://www.unboundmedicine.com/medline/citation/19302154/Tolerance_to_non_opioid_analgesics_in_PAG_involves_unresponsiveness_of_medullary_pain_modulating_neurons_in_male_rats_ L2 - https://doi.org/10.1111/j.1460-9568.2009.06678.x DB - PRIME DP - Unbound Medicine ER -