title: Evidence for spinal dorsal horn hyperexcitability in rats following sustained morphine exposure.
abstract: Repeated or sustained exposure to opioids can not only induce analgesia but also long lasting enhancements in pain sensitivity, a phenomenon reported clinically and in animals. In rats, opioid-induced abnormal pain can be readily measured following continued delivery of morphine and the recruitment of descending facilitatory influences appears essential for the genesis of this state. Here, we provide evidence that an increased excitability develops in neurons of the deep dorsal horn (DH), following 7-10 days of sustained delivery of morphine. Electrophysiological recordings were made in halothane-anesthetised animals implanted with osmotic minipumps containing either morphine (45 microg/0.5 microl/h and 90 microg/0.5 microl/h) or saline. A separate group of naïve animals was also used as controls. Sustained morphine exposure resulted in dose-related and modality-specific enhancements of DH neurons (C-fibre and Adelta-fibre evoked responses, non-potentiated responses) and expanded neuronal receptive fields, as mapped with low intensity mechanical punctate stimuli. Heat and mechanical stimulation of the hindpaw (brush and von Frey filaments) produced similar enhancements in morphine-treated rats compared to control rats, reflecting spinal hyperexcitability. Interestingly, wind-up itself was unaltered. These neuroadaptive changes could form the neuronal basis for the documented clinical and experimental reports of abnormal paradoxical pain after opioids. Since brainstem excitatory controls actively operate during prolonged opioid exposure, the sustained triggering of such influences may act alongside spinal mechanisms such as wind-up to enhance central sensitisation and alter CNS excitability.
authors.affiliation: Department of Pharmacology, Medical Sciences Building, University College London, Gower Street, London WC1E 6BT, UK. ucklrsu@ucl.ac.uk
authors.forename: Rie
authors.initials: R
authors.lastname: Suzuki
authors.forename: Frank
authors.initials: F
authors.lastname: Porreca
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Dickenson
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004594:Electrophysiology; D006614:Hindlimb / Q000294:innervation; D006358:Hot Temperature; D009020:Morphine / Q000494:pharmacology*; D009434:Neural Pathways / Q000502:physiology; D009473:Neuronal Plasticity; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; D018040:Receptors, Neurokinin-1; D009020:Morphine