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The Journal of Neuroscience, April 19, 2006, 26(16):4298-4307; doi:10.1523/JNEUROSCI.0960-06.2006

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Cellular/Molecular
Windup in Dorsal Horn Neurons Is Modulated by Endogenous Spinal µ-Opioid Mechanisms

Yun Guan,¹ Jasenka Borzan,¹ Richard A. Meyer,^2,3 and Srinivasa N. Raja¹

Departments of¹Anesthesiology and Critical Care Medicine and ²Neurosurgery, ³Applied Physics Laboratory, Johns Hopkins University, School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. Srinivasa N. Raja, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 292 Osler, 600 North Wolfe Street, Baltimore, MD 21287. Email: sraja{at}jhmi.edu

The µ-opioid receptor (MOR) plays a critical role in morphine analgesia and nociceptive transmission. However, the physiological roles for endogenous MOR mechanisms in modulating spinal nociceptive transmission, and particularly in the enhanced excitability of spinal nociceptive neurons after repeated noxious inputs, are less well understood. Using a MOR gene knock-out (–/–) approach and an MOR-preferring antagonist, we investigated the roles of endogenous MOR mechanisms in processing of acute noxious input and in neuronal sensitization during windup-inducing stimuli in wide dynamic range (WDR) neurons. Extracellular single-unit activity of WDR neurons was recorded in isoflurane-anesthetized MOR^–/– and wild-type C57BL/6 mice. There were no significant differences between the genotypes in the responses of deep WDR cells to acute mechanical stimuli, graded electrical stimuli, and noxious chemical stimuli applied to the receptive field. Intracutaneous electrical stimulation at 1.0 Hz produced similar levels of windup in both genotypes. In contrast, 0.2 Hz stimulation induced significantly higher levels of windup in MOR^–/– mice compared with the wild-type group. In wild-type mice, spinal superfusion with naloxone hydrochloride (10 mM, 30 µl) significantly enhanced windup to 0.2 Hz stimulation in both deep and superficial WDR cells. A trend toward facilitation of windup was also observed during 1.0 Hz stimulation after naloxone treatment. These results suggest that endogenous MOR mechanisms are not essential in the processing of acute noxious mechanical and electrical stimuli by WDR neurons. However, MORs may play an important role in endogenous inhibitory mechanisms that regulate the development of spinal neuronal sensitization.

Key words: µ-opioid receptor; spinal cord; wide dynamic range neuron; pain; neuronal plasticity; transgenic mice

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Received Aug. 16, 2005; revised March 10, 2006; accepted March 10, 2006.

Correspondence should be addressed to Dr. Srinivasa N. Raja, Division of Pain Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, 292 Osler, 600 North Wolfe Street, Baltimore, MD 21287. Email: sraja{at}jhmi.edu

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