Moxonidine, a selective imidazoline/α2 adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice

Carolyn A. Fairbanks; Ivan J. Posthumus; Kelley F. Kitto; Laura S. Stone; George L. Wilcox

doi:10.1016/S0304-3959(99)00171-2

Moxonidine, a selective imidazoline/α₂ adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice

Carolyn A. Fairbanks, Ivan J. Posthumus, Kelley F. Kitto, Laura S. Stone, George L. Wilcox

Research output: Contribution to journal › Article › peer-review

47 Scopus citations

Abstract

The α₂ adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I₁/α₂ (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala- NMe-Phe-Gly(ol)) to inhibit substance P-elicted nociceptive behavior in Institute of Cancer Research mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED₅₀) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED₅₀ values of the combinations were statistically compared against their respective calculated theoretical additive ED₅₀ values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose- response curves compared to those of each agonist administered separately. The ED₅₀ values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED₅₀ values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine- opioid combinations may prove an effective therapeutic strategy to manage pain.

Original language	English (US)
Pages (from-to)	13-20
Number of pages	8
Journal	Pain
Volume	84
Issue number	1
DOIs	https://doi.org/10.1016/S0304-3959(99)00171-2
State	Published - Jan 1 2000

Bibliographical note

Funding Information:
We extend profound appreciation to Dr Dieter Ziegler for facilitation of the generous gift of moxonidine by Solvay Pharma, and to Dr Michael Ossipov for helpful discussions. This research was supported by NIH/R01-DA-01933 and NIH/R01-DA-04274, and ADAMHA training grant T32DA07234 awarded by NIDA supported CAF.

Keywords

Adrenergic
Antinociception
Moxonidine
Opioid
Spinal
Synergy

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title = "Moxonidine, a selective imidazoline/α2 adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice",

abstract = "The α2 adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I1/α2 (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala- NMe-Phe-Gly(ol)) to inhibit substance P-elicted nociceptive behavior in Institute of Cancer Research mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED50) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED50 values of the combinations were statistically compared against their respective calculated theoretical additive ED50 values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose- response curves compared to those of each agonist administered separately. The ED50 values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED50 values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine- opioid combinations may prove an effective therapeutic strategy to manage pain.",

keywords = "Adrenergic, Antinociception, Moxonidine, Opioid, Spinal, Synergy",

author = "Fairbanks, {Carolyn A.} and Posthumus, {Ivan J.} and Kitto, {Kelley F.} and Stone, {Laura S.} and Wilcox, {George L.}",

note = "Funding Information: We extend profound appreciation to Dr Dieter Ziegler for facilitation of the generous gift of moxonidine by Solvay Pharma, and to Dr Michael Ossipov for helpful discussions. This research was supported by NIH/R01-DA-01933 and NIH/R01-DA-04274, and ADAMHA training grant T32DA07234 awarded by NIDA supported CAF.",

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T1 - Moxonidine, a selective imidazoline/α2 adrenergic receptor agonist, synergizes with morphine and deltorphin II to inhibit substance P-induced behavior in mice

AU - Fairbanks, Carolyn A.

AU - Posthumus, Ivan J.

AU - Kitto, Kelley F.

AU - Stone, Laura S.

AU - Wilcox, George L.

N1 - Funding Information: We extend profound appreciation to Dr Dieter Ziegler for facilitation of the generous gift of moxonidine by Solvay Pharma, and to Dr Michael Ossipov for helpful discussions. This research was supported by NIH/R01-DA-01933 and NIH/R01-DA-04274, and ADAMHA training grant T32DA07234 awarded by NIDA supported CAF.

PY - 2000/1/1

Y1 - 2000/1/1

N2 - The α2 adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I1/α2 (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala- NMe-Phe-Gly(ol)) to inhibit substance P-elicted nociceptive behavior in Institute of Cancer Research mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED50) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED50 values of the combinations were statistically compared against their respective calculated theoretical additive ED50 values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose- response curves compared to those of each agonist administered separately. The ED50 values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED50 values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine- opioid combinations may prove an effective therapeutic strategy to manage pain.

AB - The α2 adrenergic receptor (AR) class of catecholamine/imidazoline (I) agonists, such as norepinephrine and clonidine, produce spinal antinociceptive synergy when co-administered with opioids. We have observed that intrathecally administered moxonidine, a selective I1/α2 (AR) agonist, produces antinociception. The present experiments tested moxonidine for ability to synergize with morphine, deltorphin II, and DAMGO (Tyr-D-Ala- NMe-Phe-Gly(ol)) to inhibit substance P-elicted nociceptive behavior in Institute of Cancer Research mice. Moxonidine, morphine, deltorphin II, and DAMGO inhibited substance P-elicited nociceptive behavior with full efficacy. Effective dose 50% (ED50) values were calculated and equi-effective dose ratios of the combinations moxonidine-morphine, moxonidine-deltorphin II, and moxonidine-DAMGO were determined. The interactions were tested by isobolographic analysis. The observed ED50 values of the combinations were statistically compared against their respective calculated theoretical additive ED50 values. The combinations of moxonidine-morphine and moxonidine-deltorphin II resulted in significant leftward shifts in the dose- response curves compared to those of each agonist administered separately. The ED50 values of the dose-response curves of these combinations were significantly less than the corresponding calculated theoretical additive ED50 values; these results indicated that moxonidine synergizes with both morphine and deltorphin II. In contrast, combining moxonidine with DAMGO did not increase the potencies of the agonists (in combination) when compared to the potencies of each agonist administered separately. These results indicated that the moxonidine-DAMGO interaction is subadditive. Collectively, these data demonstrate that moxonidine combined with some opioid agonists produces spinal antinociceptive synergy. Spinally administered moxonidine- opioid combinations may prove an effective therapeutic strategy to manage pain.

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KW - Moxonidine

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KW - Spinal

KW - Synergy

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