Highlights
- •We studied contribution of spinal endomorphin to opioid analgesia in rats.
- •Mu-opioids enhance spinal endomorphin release in males but not in females.
- •Released endomorphin reduces the analgesia of high-efficacy mu-opioids.
- •Findings explain variable sex dependence of opioid antinociception.
- •Findings could inform the selection of opioid analgesics in humans.
Abstract
Interactions between exogenous and endogenous opioids are not commonly investigated
as a basis for sexually dimorphic opioid analgesia. We investigated the influence
of spinal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, on the
spinal antinociception produced by intrathecally administered opioids. Activation
of spinal MORs facilitated spinal EM2 release. This effect was sexually dimorphic,
occurring in males but not in females. Although activational effects of testosterone
were required for opioid facilitation of spinal EM2 release in males, the absence
of this facilitation in females did not result from either insufficient levels of
testosterone or mitigating effects of estrogens. Strikingly, in males, the contribution
of spinal EM2 to the analgesia produced by intrathecally applied MOR agonists depended
on their analgesic efficacy relative to that of EM2. Spinal EM2 released by the higher
efficacy MOR agonist sufentanil diminished sufentanil's analgesic effect, whereas
EM2 released by the lower efficacy morphine had the opposite effect on spinal morphine
antinociception. Understanding antithetical contributions of endogenous EM2 to intrathecal
opioid antinociception not only enlightens the selection of opioid medications for
pain management but also helps to explain variable sex dependence of the antinociception
produced by different opioids, facilitating the acceptance of sexually dimorphic antinociception
as a basic tenet.
Perspective
The male-specific MOR-coupled enhancement of spinal EM2 release implies a parallel
ability to harness endogenous EM2 antinociception. The inferred diminished ability
of females to utilize the spinal EM2 antinociceptive system could contribute to their
greater frequency and severity of chronic pain syndromes.
Key words
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Article info
Publication history
Published online: September 02, 2015
Accepted:
August 10,
2015
Received in revised form:
August 5,
2015
Received:
April 21,
2015
Footnotes
A.K. and N.-J.L. contributed equally to this work.
This study was supported by a grant from the National Institute on Drug Abuse, R01DA027663, to A.R.G. None of the authors hold any conflicts of interest.
Identification
Copyright
© 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.
