The mechanisms underlying hyperalgesia induced by peripheral injury include both peripheral and central components. The central components of hyperalgesia (central sensitisation) is characterised by an increased excitability of spinal neurones manifested as hyperreflexia, increased receptive field sizes, decreased thresholds and prolonged afterdischarges. In this talk I will address two questions of particular relevance to the understanding of central sensitisation. Firstly I will examine whether the isolated spinal cord, in the absence of peripheral and descending inputs, can show hyperreflexia. Secondly I will review several mechanisms which may lead to increased spinal excitability during hyperalgesic states, and in particular I will consider the possible role of KCNQ potassium channels.

All the work to be discussed was performed on live Wistar rat pups (behavioural experiments) or on the in vitro hemisected spinal cord obtained from the same animals (electrophysiological experiments). Inflammations were induced in a group of animals by intraplantar injection of carrageenan (25 µl) in a hindpaw. The spinal cord was extracted under I.P. urethane anaesthesia, hemisected and maintained in vitro using standard procedures (Hedo et al. 1999). Dorsal root-ventral root reflexes (DR-VRRs) were obtained from the lumbar segments L4 or L5 using suction electrodes. Changes in these reflexes induced by an experimental inflammation performed 3, 6 or 20 h prior to the extraction of the spinal cord and by the superfusion of potassium ion channel modulators were analysed.

Induction of paw inflammation caused a behavioural hyperalgesia to mechanical stimuli which developed shortly after the injection of carrageenan and lasted for more than 20 h. The DR-VRRs obtained from animals that had suffered an inflammation 6 or 20 h (but not 3 h) prior to extraction of the spinal cord were significantly greater than those obtained from naive animals. This observation indicates that the consolidation of memory traces of injury in the spinal cord requires prolonged time periods which are consistent with the synthesis, trafficking and/or phosphorylation of relevant synaptic proteins. The nature of these relevant proteins and the processes involved in their regulation are not fully established at present.

KCNQ proteins are the molecular substrate for M-currents, which are known to be involved in the regulation of neuronal excitability. Ongoing work in our laboratory using isolated spinal cords from naive animals shows that superfusion of XE-991, an M-current blocker (Zaczek et al. 1998), enhances spinal reflexes whereas superfusion of retigabine, an M-current opener (Rundfelt, 1997), produces inhibition of reflexes. These experiments indicate the presence of functional M-currents in the spinal cord and bring into focus the possible role that these currents may play during altered algesic states.

This work was supported by the Spanish Ministry of Science and Technology (SAF-2000-0199), the Madrid Regional Government (Contrato Programa, Principal investigator: Dr F. Cervero) and Instituto UPSA del Dolor.