Elsevier

Neuroscience

Volume 100, Issue 4, 11 October 2000, Pages 861-871
Neuroscience

Bi-directional changes in affective state elicited by manipulation of medullary pain-modulatory circuitry

https://doi.org/10.1016/S0306-4522(00)00329-8Get rights and content

Abstract

The rostral ventromedial medulla contains three physiologically defined classes of pain-modulating neuron that project to the spinal and trigeminal dorsal horns. OFF cells contribute to anti-nociceptive processes, ON cells contribute to pro-nociceptive processes (i.e. hyperalgesia) and neutral cells tonically modulate spinal nociceptive responsiveness. In the setting of noxious peripheral input, the different cell classes in this region permit bi-directional modulation of pain perception (analgesia vs hyperalgesia). It is unclear, however, whether changes in the activity of these neurons are relevant to the behaving animal in the absence of a painful stimulus. Here, we pharmacologically manipulated neurons in the rostral ventromedial medulla and used the place-conditioning paradigm to assess changes in the affective state of the animal. Local microinjection of the α1-adrenoceptor agonist methoxamine (50.0 μg in 0.5 μl; to activate ON cells, primarily), combined with local microinjection of the κ-opioid receptor agonist U69,593 (0.178 μg in 0.5 μl; to inhibit OFF cells), produced an increase in spinal nociceptive reactivity (i.e. hyperalgesia on the tail flick assay) and a negative affective state (as inferred from the production of conditioned place avoidance) in the conscious, freely moving rat. Additional microinjection experiments using various concentrations of methoxamine alone or U69,593 alone revealed that the rostral ventromedial medulla is capable of eliciting a range of affective changes resulting in conditioned place avoidance, no place-conditioning effect or conditioned place preference (reflecting production of a positive affective state). Overall, however, there was no consistent relationship between place-conditioning effects and changes in spinal nociceptive reactivity.

This is the first report of bi-directional changes in affective state (i.e. reward or aversion production) associated with pharmacological manipulation of a brain region traditionally associated with bi-directional pain modulation. We conclude that, in addition to its well-described pain-modulating effects, the rostral ventromedial medulla is capable of modifying animal behavior in the absence of a painful stimulus by bi-directionally influencing the animal’s affective state.

Section snippets

Subjects

Subjects were male Long–Evans rats (Simonsen Laboratory, Gilroy, CA) weighing 275–350 g at the start of the experiment. Rats were housed three per cage on a 12 h/12 h light–dark schedule with food and water available ad libitum. All experiments were carried out with the approval of the Institutional Animal Care and Use Committee at the University of California, San Francisco. All efforts were made to minimize animal suffering and to reduce the number of animals used.

Surgery

Under ketamine hydrochloride

Microinjection of methoxamine (50 μg) into the rostral ventromedial medulla

The purpose of this experiment was to activate RVM ON cells pharmacologically and determine the effect of this manipulation on the affective state of the animal. We hypothesized that, in the absence of significant noxious input from the periphery, activation of RVM ON cells would be sufficient to activate nociceptive neurons in the spinal and trigeminal dorsal horns, including nociceptive neurons projecting to supraspinal targets. The production of this nociceptive signal was to be indexed in

Summary of results

Co-administration of the α1-adrenergic receptor agonist MTX (50 μg) and the κ-opioid receptor agonist U69,593 (0.178 μg) into the RVM resulted in both hyperalgesia on the rat TF assay and CPA (Fig. 6). These data support our hypothesis (see Introduction) that pharmacological manipulation of RVM neurons can elicit a “virtual” nociceptive (pain?) signal by activating nociceptive neurons in the spinal dorsal horn. However, results from additional experiments using intra-RVM microinjections of

Acknowledgements

This work was supported by grants from the US Public Health Service (NS 21445, NS 07265), the Wheeler Center for the Neurobiology of Addiction and the Medical Research Council of Canada. N.H. was supported by a postdoctoral fellowship from the Ministry of Education, Science and Culture, Japan.

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    *

    Present address: Department of Anesthesiology and Critical Care Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan.

    Present address: Department of Psychology, Western New England College, Box 5249, Springfield, MA 01040, USA.

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