Bi-directional changes in affective state elicited by manipulation of medullary pain-modulatory circuitry
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.
References (45)
- et al.
The raphe nuclei of the cat brain stem: a topographical atlas of their efferent projections as revealed by autoradiography
Brain Res.
(1976) The relationship between descending serotonin projections and ascending projections in the nucleus raphe magnus: a double labeling study
Neurosci. Lett.
(1986)Dose-dependent effects of morphine differentiate self-administration elicited from lateral hypothalamus and mesencephalic central gray area in mice
Brain Res.
(1990)- et al.
Afferent and efferent connections of the medial preoptic area in the rat: a WGA–HRP study
Brain Res. Bull.
(1985) - et al.
Infusions of 6-hydroxydopamine into the nucleus accumbens abolish the analgesic effect of amphetamine but not of morphine in the formalin test
Brain Res.
(1992) - et al.
Conditioned place aversion produced by microinjections of semicarbazide into the periaqueductal gray of the rat
Brain Res.
(1989) Analgesia and abuse potential: an accidental association or a common substrate?
Pharmac. Biochem. Behav.
(1998)- et al.
A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia
Pain
(1988) - et al.
Forebrain projections of the rostral nucleus raphe magnus shown by iontophoretic application of cholera toxin b in rats
Neurosci. Lett.
(1996) - et al.
Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of cholera toxin (subunit b)
J. chem. Neuroanat.
(1997)
Two distinct unit activity responses to morphine in the rostral ventromedial medulla of awake rats
Brain Res.
The contribution of the rostral ventromedial medulla to the antinociceptive effects of systemic morphine in restrained and unrestrained rats
Neuroscience
Circuitry linking opioid-sensitive nociceptive modulatory systems in periaqueductal gray and spinal cord with rostral ventromedial medulla
Neuroscience
Effects of pedunculopontine tegmental nucleus lesions on morphine-induced conditioned place preference and analgesia in the formalin test
Neuroscience
Evidence for pain modulation by pre- and postsynaptic noradrenergic receptors in the medulla oblongata
Brain Res.
Ascending and cerebellar non-serotonergic projections from the nucleus raphe magnus of the rat
Brain Res.
Ascending components of the medial forebrain bundle from the lower brain stem in the rat, with special reference to raphe and catecholamine cell groups. A study by the HRP method
Brain Res.
Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues
Prog. Neurobiol.
A lectin horseradish peroxidase study of the origin of ascending fibers in the medial forebrain bundle of the rat. The lower brainstem
Neuroscience
α1-Adrenoceptor subtypes
Eur. J. Pharmac.
Afferent connections of the rostral medulla of the cat: a neural substrate for midbrain–medullary interactions in the modulation of pain
J. comp. Neurol.
Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens
Crit. Rev. Neurobiol.
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Present address: Department of Anesthesiology and Critical Care Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan.
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Present address: Department of Psychology, Western New England College, Box 5249, Springfield, MA 01040, USA.