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Joint manipulation reduces hyperalgesia by activation of monoamine receptors but not opioid or GABA receptors in the spinal cord

Skyba, A D.a,c; Radhakrishnan, Rb,c; Rohlwing, J J.b; Wright, Ad; Sluka, A K.a,b,c,∗

doi: 10.1016/S0304-3959(03)00320-8

Joint manipulation has long been used for pain relief. However, the underlying mechanisms for manipulation-related pain relief remain largely unexplored. The purpose of the current study was to determine which spinal neurotransmitter receptors mediate manipulation-induced antihyperalgesia. Rats were injected with capsaicin (50 μl, 0.2%) into one ankle joint and mechanical withdrawal threshold measured before and after injection. The mechanical withdrawal threshold decreases 2 h after capsaicin injection. Two hours after capsaicin injection, the following drugs were administered intrathecally: bicuculline, blocks γ-aminobutyric acid (GABAA) receptors; naloxone, blocks opioid receptors; yohimbine blocks, α2-adrenergic receptors; and methysergide, blocks 5-HT1/2 receptors. In addition, NAN-190, ketanserin, and MDL-72222 were administered to selectively block 5-HT1A, 5-HT2A, and 5-HT3 receptors, respectively. Knee joint manipulation was performed 15 min after administration of drug. The knee joint was flexed and extended to end range of extension while the tibia was simultaneously translated in an anterior to posterior direction. The treatment group received three applications of manipulation, each 3 min in duration separated by 1 min of rest. Knee joint manipulation after capsaicin injection into the ankle joint significantly increases the mechanical withdrawal threshold for 45 min after treatment. Spinal blockade of 5-HT1/2 receptors with methysergide prevented, while blockade of α2-adrenergic receptors attenuated, the manipulation-induced antihyperalgesia. NAN-190 also blocked manipulation-induced antihyperalgesia suggesting that effects of methysergide are mediated by 5-HT1A receptor blockade. However, spinal blockade of opioid or GABAA receptors had no effect on manipulation induced-antihyperalgesia. Thus, the antihyperalgesia produced by joint manipulation appears to involve descending inhibitory mechanisms that utilize serotonin and noradrenaline.

aNeuroscience Graduate Program, University of Iowa, Iowa City, IA, USA

bPhysical Therapy and Rehabilitation Science Graduate Program, University of Iowa, 1–252 Medical Education Building, Iowa City, IA 52242–1190, USA

cPain Research Program, University of Iowa, Iowa City, IA, USA

dSchool of Physiotherapy, Curtin University of Technology, Perth, WA, Australia

Corresponding author. Address: Physical Therapy and Rehabilitation Science Graduate Program, University of Iowa, 1–252 Medical Education Building, Iowa City, IA 52242–1190, USA. Tel.: +1–319–335–9791; fax: +1–319–335–9707


Submitted May 9, 2003; revised July 21, 2003; accepted July 30, 2003.

© 2003 Lippincott Williams & Wilkins, Inc.
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