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  • Review Article
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State-dependent opioid control of pain

Key Points

  • Opioid receptors are a family of related G-protein-coupled receptors. Both endogenous and exogenous ligands for these receptors have powerful motivational actions.

  • Opioid actions on nociceptive transmission are exerted through a circuit that connects limbic forebrain and brainstem structures to spinal and trigeminal dorsal horn.

  • μ-Opioid receptor agonists act at sites that are distributed throughout this circuit to produce analgesia. This effect involves the release of endogenous opioids at serially connected brainstem and spinal sites.

  • This circuit can exert bidirectional control through on cells that facilitate and off cells that inhibit nociceptive transmission.

  • The action of selective κ-(KOR) and ORL1 receptor agonists depends on the state of the circuit. When the circuit is in the pain-facilitating on-cell state, both KOR and ORL1 agonists have a pain-reducing effect. When the circuit is in the off-cell (pain suppressing) state, these same agonists reduce analgesia.

  • The opioid-mediated off-cell state is robustly activated by both aversive and appetitive motivational states. The reversal of placebo analgesia by naloxone indicates that it might be an example of an appetitive state.

Abstract

Agonists for the μ-opioid receptor are powerful analgesics and are highly addictive; however, the contribution of the δ- and κ-opioid and opioid receptor-like receptors to motivational states is less clear. Agonists at each receptor modulate neurons in a circuit that selectively controls nociceptive transmission. This circuit can operate in both pain-inhibiting and pain-facilitating states, and the action of opioids contributes to and is determined by the state of the circuit. There is growing evidence that the state of the circuit is determined by aversive and appetitive motivational states, and that this contributes to adaptive behavioural choice.

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Figure 1: Schematic of afferent pathways underlying the sensation of pain.
Figure 2: Outline of opioid-sensitive pain-modulating circuit.
Figure 3: Synaptic actions of μ-opioid receptor (MOR) agonists in the rostral ventromedial medulla (RVM).
Figure 4: Two populations of neurons exert opposing modulatory actions.
Figure 5: Shifts in nociceptive modulatory state during morphine analgesia and acute naloxone-induced abstinence.

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Acknowledgements

The author would like to thank M. Heinricher for useful discussions and for calling attention to several relevant references. The author is supported by PHS grants and the State of California Alcohol and Addiction Research Program at the University of California.

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DATABASES

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OPRD

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OPRL

OPRM

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Glossary

LIMBIC

A term that refers to a collection of cortical and subcortical structures that are important for processing memory and emotional information. Prominent structures include the hippocampus and amygdala.

AMYGDALA

A small almond-shaped structure, comprising 13 nuclei, buried in the anterior medial section of each temporal lobe.

G PROTEIN

A heterotrimeric GTP-binding and -hydrolysing protein that interacts with cell-surface receptors, often stimulating or inhibiting the activity of a downstream enzyme. G proteins consist of three subunits: the α-subunit, which contains the guanine-nucleotide-binding site; and the β- and γ-subunits, which function as a heterodimer.

INWARDLY RECTIFYING POTASSIUM CHANNELS

Potassium channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.

BASAL GANGLIA

A group of interconnected subcortical nuclei in the forebrain and midbrain that includes the striatum (putamen and caudate nucleus), globus pallidus, subthalamic nucleus, ventral tegmental area and substantia nigra.

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Fields, H. State-dependent opioid control of pain. Nat Rev Neurosci 5, 565–575 (2004). https://doi.org/10.1038/nrn1431

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