The nociceptive responses of rat ventrobasal thalamus neurons can be reduced by N-methyl-D-aspartate antagonists and by selective metabotropic glutamate receptor mGlu1 antagonists. The recent development of the mGlu5-selective antagonist 6-methyl-2-(phenylethynyl)-pyridine now allows the direct probing of the possible involvement of mGlu5 receptors in thalamic nociceptive responses. Extracellular recordings were made from single neurons in the ventrobasal thalamus and immediately overlying dorsal thalamic nuclei of adult urethane-anaesthetized rats using multi-barrel electrodes. Responses of neurons to iontophoretic applications of the mGlu5-selective agonist (R,S)-2-chloro-5-hydroxyphenylglycine were selectively reduced during continuous iontophoretic applications of 6-methyl-2-(phenylethynyl)-pyridine. Similar applications of 6-methyl-2-(phenylethynyl)-pyridine reduced neuronal responses to noxious thermal stimuli to 53+/-9.5% of control responses. Co- application by iontophoresis of N-methyl-D-aspartate and metabotropic glutamate receptor agonists resulted in a mutual potentiation of excitatory responses. This effect could be reduced by either 6-methyl-2-(phenylethynyl)-pyridine or the mGlu1 antagonist LY367385. These results, taken together with previous data, suggest that acute thalamic nociceptive responses are mediated by a combination of mGlu1, mGlu5 and N-methyl-D-aspartate receptor activation, and that co-activation of these receptors produces a synergistic excitatory effect. Thus blockade of any of these receptor types would have a profound effect on the overall nociceptive response.