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Division of Animal Physiology, School of Biosciences and Institute of Neuroscience, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK

This study assessed the involvement of NMDA and group I metabotropic glutamate receptors, and tachykinin NK₁ and NK₃ receptors, in central sensitization of withdrawal reflexes in the decerebrated rabbit. Reflexes evoked in the ankle flexor tibialis anterior and the knee flexor semitendinosus by electrical stimulation at the base of the toes were enhanced for 29–63 min after application of 20% mustard oil to the tips of the toes. Selective antagonists of mGlu₁, mGlu₅, NMDA and NR2B-subunit-containing NMDA glutamate receptors, as well as NK₁, and NK₃ receptors, and a non-selective blocker of all tachykinin receptors, were assessed for their effects on the magnitude and duration of the increase in reflexes induced by mustard oil. Dizocilpine, an antagonist of all NMDA receptors (1 mg intrathecal) abolished facilitation of tibialis anterior reflexes and significantly reduced the magnitude and duration of increase of the semitendinosus response. The NR2B-subtype selective antagonist CP-101,606 decreased the magnitude of facilitation of both reflexes but had no effect on duration of enhancement. Selective antagonists for the mGlu₁ (CPCCOEt, 1–3 mg intrathecal), mGlu₅ (MPEP, 0.2–1 mg intrathecal), NK₁ (L-733,060, 0.3 mg intrathecal) or NK₃ (SR 142,801, 1 mg kg^–1I.V.) receptors had no effect on the amplitude or duration of sensitization. However, the non-selective tachykinin receptor blocker ZD-6021 (0.3 mg intrathecal) reduced the amplitude but not the duration of sensitization in the flexor reflexes. Combination of ZD-6021 with CP-101,606 (doses as above) decreased both aspects of the sensitization response. Dizocilpine reduced reflexes evoked from the heel per se, and dizocilpine, CP-101,606 and ZD-6021 reduced arterial blood pressure. Otherwise the drugs used had no effects on baseline variables. The present data confirm the importance of NMDA receptors as a critical part of the process of central sensitization, provide no evidence for a role of metabotropic glutamate receptors, and show that simultaneous blockade of all tachykinin receptors is required to reveal their role in hyperalgesia. The data further indicate that a combined pharmacological approach offers a potential way forward for the development of new antihyperalgesic agents.

(Received 18 August 2003; accepted after revision 15 December 2003)
Corresponding author R. W. Clarke: Division of Animal Physiology, School of Biosciences and Institute of Neuroscience, University of Nottingham, Sutton Bonington Campus, Loughborough, LE12 5RD, UK. Email: robert.clarke{at}nottingham.ac.uk