Sustained Morphine Exposure Induces a Spinal Dynorphin-Dependent Enhancement of Excitatory Transmitter Release from Primary Afferent Fibers

• Published in: The Journal of neuroscience Vol. 22; no. 15; pp. 6747 - 6755
• Main Authors: Gardell, Luis R, Wang, Ruizhong, Burgess, Shannon E, Ossipov, Michael H, Vanderah, Todd W, Malan, T. Philip, Jr, Lai, Josephine, Porreca, Frank
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 01.08.2002; Society for Neuroscience
• Subjects: Animals; Behavior, Animal - drug effects; Calcitonin Gene-Related Peptide - metabolism; Drug Implants; Drug Tolerance; Dynorphins - antagonists & inhibitors; Dynorphins - metabolism; Dynorphins - pharmacology; Hot Temperature; Hyperalgesia - chemically induced; Hyperalgesia - metabolism; Immune Sera - pharmacology; In Vitro Techniques; Male; Morphine - administration & dosage; Nerve Crush; Nerve Fibers - drug effects; Nerve Fibers - metabolism; Neuronal Plasticity - drug effects; Neurons, Afferent - drug effects; Neurons, Afferent - metabolism; Neurotransmitter Agents - metabolism; Pain Measurement - drug effects; Peptide Fragments - pharmacology; Physical Stimulation; Rats; Rats, Sprague-Dawley; Spinal Cord - drug effects; Spinal Cord - physiology; Time Factors
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/jneurosci.22-15-06747.2002

Paradoxical opioid-induced pain has been demonstrated repeatedly in humans and animals. The mechanisms of such pain are unknown but may relate to opioid-induced activation of descending pain facilitatory systems and enhanced expression and pronociceptive actions of spinal dynorphin. Here, the possibility that these opioid-induced central changes might mediate increased excitability to the spinal cord was tested. Tactile and thermal hypersensitivity was observed at 7, but not 1, days after subcutaneous morphine pellet implantation; placebo pellets produced no effects. Basal and capsaicin-evoked release of calcitonin gene-related peptide (CGRP) was measured in minced spinal tissues taken from naive rats or rats on post-pellet days 1 and 7. The content and evoked release of CGRP were significantly increased in tissues from morphine-exposed rats at 7, but not 1, days after implantation. Morphine increased spinal dynorphin content on day 7 in rats with sham bilateral lesions of the dorsolateral funiculus (DLF) but not in rats with DLF lesions. Pharmacological application of dynorphin A(2-13), a non-opioid fragment, to tissues from naive rats enhanced the evoked release of CGRP. Enhanced evoked release of CGRP from morphine-pelleted rats was blocked by dynorphin antiserum or by previous lesions of the DLF. Sustained morphine induces plasticity in both primary afferents and spinal cord, including increased CGRP and dynorphin content. Morphine-induced elevation of spinal dynorphin content depends on descending influences and enhances stimulated CGRP release. Enhanced transmitter release may allow increased stimulus-evoked spinal excitation, which is likely to be critical for opioid-induced paradoxical pain. Such pain may manifest behaviorally as antinociceptive tolerance.