Morphine-induced spinal cholinergic activation: in vivo imaging with positron emission tomography

Positron emission tomography (PET) imaging of spinal cord in monkeys with a cholinergic tracer demonstrates increased spinal cholinergic activity in r esponse to an analgesic dose of morphine, and this PET result correlates wi th measurement of acetylcholine spillover into spinal cord extracellular sp ace induced by morphine, as measured by microdialysis. Previous studies in rats, mice, and sheep demonstrate activation of spinal cholinergic neurons by systemic opioid administration, and participation of this cholinergic ac tivity in opioid-induced analgesia. Testing the relevance of this observati on in humans has been limited to measurement of acetylcholine spillover int o lumbar cerebrospinal fluid, The purpose of this study was to apply a rece ntly developed method to image spinal cholinergic terminals non-invasively via PET and to test the hypothesis that the tracer utilized would reflect c hanges in local cholinergic activity. Following Animal Care and Use Committ ee approval, seven adult male rhesus monkeys were anesthetized on three sep arate occasions. On two of the occasions PET scans were performed using [F- 18] (+)-4-fluorobenzyltrozamicol ([F-18]FBT), which selectively binds to th e vesicular acetylcholine (ACh) transporter in the presynaptic cholinergic terminals. PET scans were preceded by injection of either saline or an anal gesic dose of IV morphine (10 mg/kg). On the third occasion, microdialysis catheters were inserted in the spinal cord dorsal horn and acetylcholine co ncentrations in dialysates determined before and after IV morphine injectio n, Morphine increased cholinergic activity in the spinal cord, as determine d by blood flow corrected distribution volume of [F-18]FBT in the cervical cord compared to the cerebellum. Morphine also increased acetylcholine conc entrations in microdialysates from the cervical cord dorsal horn. The one a nimal which did not show increased spinal cholinergic activity by PET from this dose of morphine also did not show increased acetylcholine from this m orphine dose in the microdialysis experiment. These data confirm the abilit y to use PET to image spinal cholinergic terminals in the monkey spinal cor d and suggest that acute changes in cholinergic activity can be imaged with this non-invasive technique. Following preclinical screening, PET scanning with [F-18]FBT may be useful to investigate mechanisms of analgesic action in normal humans and in those with pain. (C) 2001 International Associatio n for the Study of Pain. Published by Elsevier Science B.V. All rights rese rved.