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PMID: 11150345 Published · ppublish English Journal Article

Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 21 ·No. 1 ·2001-01-01 ·Pages 279-86

Vanderah TW, Suenaga NM, Ossipov MH, Malan TP, Lai J, Porreca F

Abstract

Many clinical case reports have suggested that sustained opioid exposure can elicit unexpected, paradoxical pain. Here, we explore the possibility that (1) opioid-induced pain results from tonic activation of descending pain facilitation arising in the rostral ventromedial medulla (RVM) and (2) the presence of such pain manifests behaviorally as antinociceptive tolerance. Rats implanted subcutaneously with pellets or osmotic minipumps delivering morphine displayed time-related tactile allodynia and thermal hyperalgesia (i. e., opioid-induced "pain"); placebo pellets or saline minipumps did not change thresholds. Opioid-induced pain was observed while morphine delivery continued and while the rats were not in withdrawal. RVM lidocaine, or bilateral lesions of the dorsolateral funiculus (DLF), did not change response thresholds in placebo-pelleted rats but blocked opioid-induced pain. The intrathecal morphine antinociceptive dose-response curve (DRC) in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats, indicating antinociceptive "tolerance." RVM lidocaine or bilateral DLF lesion did not alter the intrathecal morphine DRC in placebo-pelleted rats but blocked the rightward displacement seen in morphine-pelleted animals. The subcutaneous morphine antinociceptive DRC in morphine-pelleted rats was displaced to the right of that in placebo-pelleted rats; this right shift was blocked by RVM lidocaine. The data show that (1) opioids elicit pain through tonic activation of bulbospinal facilitation from the RVM, (2) increased pain decreases spinal opioid antinociceptive potency, and (3) blockade of pain restores antinociceptive potency, revealing no change in antinociceptive signal transduction. These studies offer a mechanism for paradoxical opioid-induced pain and allow the development of approaches by which the loss of analgesic activity of opioids might be inhibited.

MeSH Terms
Analgesics/administration & dosage Animals Dose-Response Relationship, Drug Drug Implants Drug Tolerance Hot Temperature Hyperalgesia/chemically induced,physiopathology Lidocaine/administration & dosage Male Medulla Oblongata/drug effects,physiopathology Microinjections Morphine/administration & dosage,adverse effects Narcotics/administration & dosage,adverse effects Nerve Crush Pain/chemically induced,physiopathology Pain Measurement/drug effects Pain Threshold/drug effects Physical Stimulation Rats Reaction Time/drug effects Spinal Cord Injuries/physiopathology
Chemicals
Analgesics Drug Implants Narcotics Morphine Lidocaine
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Vanderah T W
Departments of Pharmacology and Anesthesiology, University of Arizona, Tucson, Arizona, 85724, USA.
Suenaga N M
Ossipov M H
Malan T P
Lai J
Porreca F
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
Published
2001-01-01
Pages
279-86
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6762454
Subset
IM
External Links
PubMed source PMC Full Text View journal details
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