Chronic pain is still a major problem in modern medicine.
Enhanced sensitivity to pain may persist long after the disappearance of the initial cause for pain. Then, pain is no longer a symptom but rather a disease on its own. Hyperalgesia (enhanced pain sensitivity to noxious stimuli) and allodynia (pain in response to normally innocuous stimuli) may persist for long periods of time due to altered processing of nociceptive information at the spinal cord level. In the spinal cord, nociceptive information is dynamically modulated by various mechanisms on a cellular or network level. This neuronal plasticity comprises a key feature of the nociceptive system. An intensively studied model of neuronal plasticity is synaptic long-term potentiation (LTP), defined as an increase in synaptic transmission efficacy lasting for days to months but at least 30 min. It has been suggested that LTP at synapses between primary afferent fibres and second order neurons in the superficial laminae of the spinal cord dorsal horn represents a model for some forms of afferent induced hyperalgesia. This hypothesis has been challenged, as LTP was experimentally induced with high-frequency, burst-like discharges at virtually all synapses studied so far. Nociceptive C-fibres, however, typically discharge at low frequencies. In the present study, it is demonstrated using C-fibre evoked field potential recordings in spinal laminae I/II of deeply anaesthetized rats that LTP is induced by electrical low-frequency stimulation of afferent fibres as well as by natural noxious stimulation. Examination of signal transduction pathways underlying the induction of LFS-induced LTP revealed that pain pathways activated during this process are of striking similarity to those known to be activated during hyperalgesia. This is consistent with a role of LTP at spinal synapses of C-fibres for pain amplification. Opioids are the mainstays for the treatment of moderate to severe pain.
A growing body of evidence suggests, however, that opioids may also elicit hyperalgesia. Here, we discovered two novel effects of the -opioid receptor agonist remifentanil on spinal nociception. We show that remifentanil exerts a bidirectional effect on spinal nociception depending on the functional state of the spinal cord.
C-fibre evoked field potentials were again recorded from deeply anaesthetized animals. In the normal animal, wash-out of remifentanil after i.v. administration led to potentiation of field potentials. This may represent a cellular model for the phenomenon of opioid-induced hyperalgesia. In contrast, remifentanil administered after LTP had been induced by different stimuli, led to depotentiation of LTP. This novel opioid action also had a behavioural correlate as enhanced nociceptive reflexes were normalised after a brief application of remifentanil.
As opioids are widely used in clinical routine, the exploration of mechanisms of both opioid effects done in the present study and the possible translation of this knowledge into clinical applications might greatly improve the use of opioids for more targeted treatment of various causes of pain. The potential of opioids to reverse established LTP could accomplish a causal therapy for some forms of enhanced pain sensitivity in patients. Parts of this study have been published in Science, 2006, 312(5780):1659-62 and Molecular Pain, 2008, 4(1):18.