Differential susceptibility of the PAG and RVM to tolerance to the antinociceptive effect of morphine in the rat

Morgan, Michael M.; Clayton, Cecilea C.; Boyer-Quick, Jill S.

doi:10.1016/j.pain.2004.09.039

Cited by 34 publications

(23 citation statements)

References 39 publications

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“…Although similar effects of antinociception can be produced by direct action of morphine upon the RVM (Henricher et al, 1992), tolerance to morphine was not remarkably obtained by repeated microinjection into the RVM (Morgan et al, 2005). Furthermore, inactivation of the RVM did not prevent the development of tolerance to repeated morphine microinjections into the PAG, and tolerance to systemic morphine did not develop if opioid receptors were blocked in the PAG even if the RVM remained intact (Lane et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Tsagareli¹,

Nozadze²,

Tsiklauri³

et al. 2011

Front. Neurosci.

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Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

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Section: Discussionmentioning

confidence: 99%

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Tsagareli¹,

Nozadze²,

Tsiklauri³

et al. 2011

Front. Neurosci.

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“…Numerous studies show that morphine microinjection into the ventral PAG produces analgesia (Jacquet and Lajtha, 1976; Yaksh et al, 1976; Lewis and Gebhart, 1977; Jensen and Yaksh, 1986; Siuciak and Advokat, 1987; Behbehani, 1995). The behavioral antinociception produced by microinjection of morphine into the vlPAG, but not the dlPAG, decreases with repeated administration (Jacquet and Lajtha, 1976; Lewis and Gebhart, 1977; Siuciak and Advokat, 1987; Tortorici et al, 1999, 2001; Morgan et al, 2005a,b), a phenomenon known as opioid tolerance. This opioid tolerance is restricted to the vlPAG, and does not occur with administration in the dlPAG (Tortorici et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats

DeSantana¹,

Silva²,

Resende³

et al. 2009

Neuroscience

139

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Transcutaneous electric nerve stimulation (TENS) is widely used for the treatment of pain. TENS produces an opioid-mediated antinociception that utilizes the rostroventromedial medulla (RVM). Similarly, antinociception evoked from the periaqueductal grey (PAG) is opioid-mediated and includes a relay in the RVM. Therefore, we investigated whether the ventrolateral or dorsolateral PAG mediates antinociception produced by TENS in rats. Paw and knee joint mechanical withdrawal thresholds were assessed before and after knee joint inflammation (3% kaolin/carrageenan), and after TENS stimulation (active or sham). Cobalt chloride (CoCl2; 5 mM) or vehicle was microinjected into the ventrolateral periaqueductal grey (vlPAG) or dorsolateral periaqueductal grey (dlPAG) prior to treatment with TENS. Either high (100 Hz) or low (4 Hz) frequency TENS was then applied to the inflamed knee for 20 min. Active TENS significantly increased withdrawal thresholds of the paw and knee joint in the group microinjected with vehicle when compared to thresholds prior to TENS (P<0.001) or to sham TENS (P<0.001). The increases in withdrawal thresholds normally observed after TENS were prevented by microinjection of CoCl2 into the vlPAG, but not the dlPAG prior to TENS and were significantly lower than controls treated with TENS (P<0.001). In a separate group of animals, microinjection of CoCl2 into the vlPAG temporarily reversed the decreased mechanical withdrawal threshold suggesting a role for the vlPAG in the facilitation of joint pain. No significant difference was observed for dlPAG. We hypothesize that the effects of TENS are mediated through the vlPAG that sends projections through the RVM to the spinal cord to produce an opioid-mediated analgesia.

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“…Although similar effects can be produced by a direct action of morphine upon the RVM (Heinricher et al. , 1992), tolerance to morphine is remarkably difficult to obtain by repeated microinjection into the RVM (Morgan et al. , 2005).…”

Section: Discussionmentioning

confidence: 99%

Tolerance to non‐opioid analgesics in PAG involves unresponsiveness of medullary pain‐modulating neurons in male rats

Tortorici

Aponte

Acevedo

et al. 2009

Eur J of Neuroscience

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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.

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Differential susceptibility of the PAG and RVM to tolerance to the antinociceptive effect of morphine in the rat

Cited by 34 publications

References 39 publications

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus

Transcutaneous electrical nerve stimulation at both high and low frequencies activates ventrolateral periaqueductal grey to decrease mechanical hyperalgesia in arthritic rats

Tolerance to non‐opioid analgesics in PAG involves unresponsiveness of medullary pain‐modulating neurons in male rats

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