Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat

Scott J. Thompson; Mark H. Pitcher; Laura S. Stone; Farid Tarum; Gang Niu; Xiaoyuan Chen; Dale O. Kiesewetter; Petra Schweinhardt; M. Catherine Bushnell

doi:10.1097/j.pain.0000000000001282

Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat

Scott J. Thompson, Mark H. Pitcher, Laura S. Stone, Farid Tarum, Gang Niu, Xiaoyuan Chen, Dale O. Kiesewetter, Petra Schweinhardt, M. Catherine Bushnell

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

73 Scopus citations

Abstract

The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [18F]-FDPN-PET in either sham rats (n 5 17) or spared nerve injury rats (n 5 17), we confirmed reduced opioid receptor availability in the insula, caudate putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.

Original language	English (US)
Pages (from-to)	1856-1866
Number of pages	11
Journal	Pain
Volume	159
Issue number	9
DOIs	https://doi.org/10.1097/j.pain.0000000000001282
State	Published - Sep 1 2018
Externally published	Yes

Bibliographical note

Funding Information:
This research was funded by the Intramural Research Programs of the National Center for Complementary and Integrative Health (NCCIH) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. Orit Jacob-son, PhD, National Institutes of Health, assisted with the radiochemistry. Lucy Vulchanova, PhD, Assistant Professor, Department of Neuroscience, University of Minnesota, donated the rabbit-derived anti-MOR1. S. J. Thompson was supported by The Louise and Alan Edwards Foundation’s PhD Studentship in Pain Research.

Publisher Copyright:
© 2018 Lippincott Williams and Wilkins. All rights reserved.

Keywords

Anhedonia
Chronic pain
Opioid receptors
Positron emission tomography
Rat

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10.1097/j.pain.0000000000001282

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title = "Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat",

abstract = "The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [18F]-FDPN-PET in either sham rats (n 5 17) or spared nerve injury rats (n 5 17), we confirmed reduced opioid receptor availability in the insula, caudate putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.",

keywords = "Anhedonia, Chronic pain, Opioid receptors, Positron emission tomography, Rat",

author = "Thompson, {Scott J.} and Pitcher, {Mark H.} and Stone, {Laura S.} and Farid Tarum and Gang Niu and Xiaoyuan Chen and Kiesewetter, {Dale O.} and Petra Schweinhardt and {Catherine Bushnell}, M.",

note = "Funding Information: This research was funded by the Intramural Research Programs of the National Center for Complementary and Integrative Health (NCCIH) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. Orit Jacob-son, PhD, National Institutes of Health, assisted with the radiochemistry. Lucy Vulchanova, PhD, Assistant Professor, Department of Neuroscience, University of Minnesota, donated the rabbit-derived anti-MOR1. S. J. Thompson was supported by The Louise and Alan Edwards Foundation{\textquoteright}s PhD Studentship in Pain Research. Publisher Copyright: {\textcopyright} 2018 Lippincott Williams and Wilkins. All rights reserved.",

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N1 - Funding Information: This research was funded by the Intramural Research Programs of the National Center for Complementary and Integrative Health (NCCIH) and the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. Orit Jacob-son, PhD, National Institutes of Health, assisted with the radiochemistry. Lucy Vulchanova, PhD, Assistant Professor, Department of Neuroscience, University of Minnesota, donated the rabbit-derived anti-MOR1. S. J. Thompson was supported by The Louise and Alan Edwards Foundation’s PhD Studentship in Pain Research. Publisher Copyright: © 2018 Lippincott Williams and Wilkins. All rights reserved.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [18F]-FDPN-PET in either sham rats (n 5 17) or spared nerve injury rats (n 5 17), we confirmed reduced opioid receptor availability in the insula, caudate putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.

AB - The opioid system plays a critical role in both the experience and management of pain. Although acute activation of the opioid system can lead to pain relief, the effects of chronic pain on the opioid system remain opaque. Cross-sectional positron emission tomography (PET) studies show reduced availability of brain opioid receptors in patients with chronic pain but are unable to (1) determine whether these changes are due to the chronic pain itself or due to preexisting or medication-induced differences in the endogenous opioid system, and (2) identify the neurobiological substrate of reduced opioid receptor availability. We investigated these possibilities using a well-controlled longitudinal study design in rat. Using [18F]-FDPN-PET in either sham rats (n 5 17) or spared nerve injury rats (n 5 17), we confirmed reduced opioid receptor availability in the insula, caudate putamen, and motor cortex of nerve injured rats 3 months after surgery, indicating that painful neuropathy altered the endogenous opioid system. Immunohistochemistry showed reduced expression of the mu-opioid receptor, MOR1, in the caudate putamen and insula. Neither the opioid peptide enkephalin nor the neuronal marker NeuN differed between groups. In nerve-injured animals, sucrose preference, a measure of anhedonia/depression-like behavior, positively correlated with PET opioid receptor availability and MOR1-immunoreactivity in the caudate putamen. These findings provide new evidence that the altered supraspinal opioid receptor availability observed in human patients with chronic pain may be a direct result of chronic pain. Moreover, reduced opioid receptor availability seems to reflect decreased receptor expression, which may contribute to pain-induced depression.

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Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat

Abstract

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