Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain

Edita Navratilova, Jennifer Yanhua Xie, Diana Meske, Chaoling Qu, Kozo Morimura, Alec Okun, Naohisa Arakawa, Michael Ossipov, Howard L. Fields, Frank Porreca

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α<inf>2</inf>-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

Original languageEnglish (US)
Pages (from-to)7264-7271
Number of pages8
JournalJournal of Neuroscience
Volume35
Issue number18
DOIs
StatePublished - May 6 2015

Fingerprint

Gyrus Cinguli
Opioid Analgesics
Nucleus Accumbens
Pain
Reward
Dopamine
Opioid Receptors
Adrenergic Agonists
Dopamine Agents
Nerve Block
Microdialysis
Clonidine
Neuralgia
Peripheral Nerves
Synaptic Transmission
Morphine
Motivation
Therapeutics
Pharmacology

Keywords

  • Affective dimension of pain
  • Anterior cingulate cortex
  • Neuropathic pain
  • Nucleus accumbens
  • Postsurgical pain
  • Reward

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. / Navratilova, Edita; Xie, Jennifer Yanhua; Meske, Diana; Qu, Chaoling; Morimura, Kozo; Okun, Alec; Arakawa, Naohisa; Ossipov, Michael; Fields, Howard L.; Porreca, Frank.

In: Journal of Neuroscience, Vol. 35, No. 18, 06.05.2015, p. 7264-7271.

Research output: Contribution to journalArticle

Navratilova, E, Xie, JY, Meske, D, Qu, C, Morimura, K, Okun, A, Arakawa, N, Ossipov, M, Fields, HL & Porreca, F 2015, 'Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain', Journal of Neuroscience, vol. 35, no. 18, pp. 7264-7271. https://doi.org/10.1523/JNEUROSCI.3862-14.2015
Navratilova, Edita ; Xie, Jennifer Yanhua ; Meske, Diana ; Qu, Chaoling ; Morimura, Kozo ; Okun, Alec ; Arakawa, Naohisa ; Ossipov, Michael ; Fields, Howard L. ; Porreca, Frank. / Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain. In: Journal of Neuroscience. 2015 ; Vol. 35, No. 18. pp. 7264-7271.
@article{072b509075724aad843c3a01826cc20d,
title = "Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain",
abstract = "Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.",
keywords = "Affective dimension of pain, Anterior cingulate cortex, Neuropathic pain, Nucleus accumbens, Postsurgical pain, Reward",
author = "Edita Navratilova and Xie, {Jennifer Yanhua} and Diana Meske and Chaoling Qu and Kozo Morimura and Alec Okun and Naohisa Arakawa and Michael Ossipov and Fields, {Howard L.} and Frank Porreca",
year = "2015",
month = "5",
day = "6",
doi = "10.1523/JNEUROSCI.3862-14.2015",
language = "English (US)",
volume = "35",
pages = "7264--7271",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "18",

}

TY - JOUR

T1 - Endogenous opioid activity in the anterior cingulate cortex is required for relief of pain

AU - Navratilova, Edita

AU - Xie, Jennifer Yanhua

AU - Meske, Diana

AU - Qu, Chaoling

AU - Morimura, Kozo

AU - Okun, Alec

AU - Arakawa, Naohisa

AU - Ossipov, Michael

AU - Fields, Howard L.

AU - Porreca, Frank

PY - 2015/5/6

Y1 - 2015/5/6

N2 - Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

AB - Pain is aversive, and its relief elicits reward mediated by dopaminergic signaling in the nucleus accumbens (NAc), a part of the mesolimbic reward motivation pathway. How the reward pathway is engaged by pain-relieving treatments is not known. Endogenous opioid signaling in the anterior cingulate cortex (ACC), an area encoding pain aversiveness, contributes to pain modulation. We examined whether endogenous ACC opioid neurotransmission is required for relief of pain and subsequent downstream activation of NAc dopamine signaling. Conditioned place preference (CPP) and in vivo microdialysis were used to assess negative reinforcement and NAc dopaminergic transmission. In rats with postsurgical or neuropathic pain, blockade of opioid signaling in the rostral ACC (rACC) inhibited CPP and NAc dopamine release resulting from non-opioid pain-relieving treatments, including peripheral nerve block or spinal clonidine, an α2-adrenergic agonist. Conversely, pharmacological activation of rACC opioid receptors of injured, but not pain-free, animals was sufficient to stimulate dopamine release in the NAc and produce CPP. In neuropathic, but not sham-operated, rats, systemic doses of morphine that did not affect withdrawal thresholds elicited CPP and NAc dopamine release, effects that were prevented by blockade of ACC opioid receptors. The data provide a neural explanation for the preferential effects of opioids on pain affect and demonstrate that engagement of NAc dopaminergic transmission by non-opioid pain-relieving treatments depends on upstream ACC opioid circuits. Endogenous opioid signaling in the ACC appears to be both necessary and sufficient for relief of pain aversiveness.

KW - Affective dimension of pain

KW - Anterior cingulate cortex

KW - Neuropathic pain

KW - Nucleus accumbens

KW - Postsurgical pain

KW - Reward

UR - http://www.scopus.com/inward/record.url?scp=84929359391&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84929359391&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3862-14.2015

DO - 10.1523/JNEUROSCI.3862-14.2015

M3 - Article

C2 - 25948274

AN - SCOPUS:84929359391

VL - 35

SP - 7264

EP - 7271

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 18

ER -