Highlights
- •The periaqueductal gray (PAG) contributes to morphine and oxycodone antinociception.
- •PAG microinjection of methadone or buprenorphine does not produce antinociception.
- •These mu-opioid receptor agonists produce antinociception via distinct mechanisms.
- •This functionally selective antinociception contributes to opioid variability.
Abstract
Morphine and fentanyl produce antinociception in part by binding to mu-opioid receptors
in the periaqueductal gray (PAG). The present study tested the hypothesis that the
PAG also contributes to the antinociceptive effects of other commonly used opioids
(oxycodone, methadone, and buprenorphine). Microinjection of high doses of oxycodone
(32–188 μg/.4 μL) into the ventrolateral PAG of the rat produced a dose-dependent
increase in hot plate latency. This antinociception was evident within 5 minutes and
nearly gone by 30 minutes. In contrast, no antinociception was evident following microinjection
of methadone or buprenorphine into the ventrolateral PAG despite use of a wide range
of doses and test times. Antinociception was evident following subsequent microinjection
of morphine into the same injection sites or following systemic administration of
buprenorphine, demonstrating that the injections sites and drugs could support antinociception.
Antinociception to systemic, but not PAG, administration of buprenorphine occurred
in both male and female rats. These and previous data demonstrate that the mu-opioid
receptor signaling pathway for antinociception in the PAG is selectively activated
by some commonly used opioids (eg, morphine, fentanyl, and oxycodone) but not others
(eg, methadone or buprenorphine). The fact that methadone and buprenorphine produce
antinociception following systemic administration demonstrates that mu-opioid receptor
signaling varies depending on location in the nervous system.
Perspective
This study demonstrates that the PAG contributes to the antinociceptive effects of
some commonly used opioids (morphine, fentanyl, and oxycodone) but not others (methadone
or buprenorphine). Such functional selectivity in PAG-mediated opioid antinociception
helps explain why the analgesic profile of opioids is so variable.
Key words
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Article info
Publication history
Published online: August 05, 2014
Accepted:
July 30,
2014
Received in revised form:
July 15,
2014
Received:
February 2,
2014
Footnotes
N.J.L. and T.M.S. are employees of Purdue Pharma, who provided funding and buprenorphine for this study.
The authors have no conflicts of interest to declare.
Identification
Copyright
© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
