Decreased substance P and NK1 receptor immunoreactivity and function in the spinal cord dorsal horn of morphine-treated neonatal rats.
Opiate analgesic tolerance is defined as a need for higher doses of opiates to maintain pain relief after prolonged opiate exposure. Though changes in the opioid receptor undoubtedly occur during conditions of opiate tolerance, there is increasing evidence that opiate analgesic tolerance is also caused by pronociceptive adaptations in the spinal cord. We have previously observed increased glutamate release in the spinal cord dorsal horn of neonatal rats made tolerant to the opiate morphine. In this study, we investigate whether spinal substance P (SP) and its receptor, the neurokinin 1 (NK1) receptor, are also modulated by prolonged morphine exposure. Immunocytochemical studies show decreased SP- and NK1-immunoreactivity in the dorsal horn of morphine-treated rats, whereas SP mRNA in the dorsal root ganglia is not changed. Electrophysiological studies show that SP fails to activate the NK1 receptor in the morphine-treated rat. Taken together, the data indicate that chronic morphine treatment in the neonatal rat is characterized by a loss of SP effects on the NK1 receptor in lamina I of the neonatal spinal cord dorsal horn. The results are discussed in terms of compensatory spinal cord processes that may contribute to opiate analgesic tolerance.


CONCLUSIONS
This article describes anatomical and physiological changes that occur in the spinal cord dorsal horn of neonatal rats after chronic morphine treatment. These changes may represent an additional compensatory process of morphine tolerance and may represent an additional therapeutic target for the retention and restoration of pain relief with prolonged morphine treatment.
Thomson
Lisa M
LM
Department of Anesthesiology, University of Washington School of Medicine, Seattle, Washington, USA.
Terman
Gregory W
GW
Zeng
Jinsong
J
Lowe
Janet
J
Chavkin
Charles
C
Hermes
Sam M
SM
Hegarty
Deborah M
DM
Aicher
Sue A
SA
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D007150:Immunohistochemistry; D009020:Morphine / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects* / Q000378:metabolism; D013373:Substance P / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
D000701:Analgesics, Opioid; D012333:RNA, Messenger; D018040:Receptors, Neurokinin-1; D013373:Substance P; D009020:Morphine