Ketamine blocks enhancement of spinal long-term potentiation in chronic opioid treated rats.

BACKGROUND: Long-term opioid treatment is associated with the development of hyperalgesia. In a rat model we wanted to study if chronic opioid treatment changed the induction and maintenance of spinal long-term potentiation (LTP), a form of hyperexcitability in the spinal cord. We also wanted to investigate if the clinically available NMDA receptor antagonist ketamine inhibited the effect of chronic opioid treatment on LTP. METHODS: The animals were randomized into four groups (saline, morphine 20 mg/kg/day, ketamine 20 mg/kg/day, morphine 20 mg/kg/day and ketamine 20 mg/kg/day). Drugs were given as continuous subcutaneous infusions by means of osmotic minipumps. After 7 days of treatment and during ongoing treatment single unit extracellular recordings were made from the lumbar deep dorsal horn under urethane anesthesia. Single electrical stimuli were applied to the sciatic nerve, and the C-fiber evoked responses of WDR neurons were recorded before and during 3 h following low frequency (3 Hz) electrical conditioning stimulation. RESULTS: The potentiation of C-fiber evoked responses by conditioning stimulation was significantly increased in the morphine-treated group compared to the saline group, while there was no significant difference between the saline, the ketamine and the morphine/ketamine groups. The potentiated responses in the morphine/ketamine group were significantly reduced compared to the morphine group (P=0.01). CONCLUSION: Our results indicate that animals treated with long-term opioid show amplification of stimulus-induced central sensitisation compared to opioid naïve animals. Ketamine inhibited the morphine-induced enhancement of LTP, supporting the role of ketamine in prevention of opioid induced hyperalgesia.

Stability of long term facilitation and expression of zif268 and Arc in the spinal cord dorsal horn is modulated by conditioning stimulation within the physiological frequency range of primary afferent fibers.

Long term facilitation (LTF) of C-fiber-evoked firing of wide dynamic range neurons in the spinal dorsal horn in response to conditioning stimulation (CS) of afferent fibers is a widely studied cellular model of spinal nociceptive sensitization. Although 100 Hz CS of primary afferent fibers is commonly used to induce spinal cord LTF, this frequency exceeds the physiological firing range. Here, we examined the effects of electrical stimulation of the sciatic nerve within the physiological frequency range on the magnitude and stability of the C-fiber-evoked responses of wide dynamic range neurons and the expression of immediate early genes (c-fos, zif268, and Arc) in anesthetized rats. Stimulation frequencies of 3, 30 and 100 Hz all induced facilitation of similar magnitude as recorded at 1 h post-CS. Strikingly, however, 3 Hz-induced potentiation of the C-fiber responses was decremental, whereas both 30 and 100 Hz stimulation resulted in stable, non-decremental facilitation over 3 h of recording. The number of dorsal horn neurons expressing c-fos, but not zif268 or Arc, was significantly elevated after 3 Hz CS and increased proportionally with stimulation rate. In contrast, a stable LTF of C-fiber responses was obtained at 30 and 100 Hz CS, and at these frequencies there was a sharp increase in zif268 expression and appearance of Arc-positive neurons. The results show that response facilitation can be induced by stimulation frequencies in the physiological range (3 and 30 Hz). Three hertz stimulation induced the early phase of LTF, but the responses were decremental. Arc and zif268, two genes previously coupled to LTP of synaptic transmission in the adult brain, are upregulated at the same frequencies that give stable LTF (30 and 100 Hz). This frequency-dependence is important for understanding how the afferent firing pattern affects neuronal plasticity and nociception in the spinal dorsal horn.