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Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.

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These electrophysiological results show that the development of inflammation following peripheral injection of carrageenan into the paw is accompanied by alterations in the magnitude of the C-fibre evoked response of multireceptive dorsal horn neurones. The evoked response of the dorsal horn cells was found to either increase or decrease in the 3 h following the carrageenan injection, and the direction of this change was related to the degree of wind-up exhibited by the cell. Regardless of whether a cell was facilitated or inhibited by carrageenan, mu, delta and kappa opioids applied topically onto the spinal cord (equivalent to an intrathecal injection) exhibited increased antinociceptive potency. This increased effectiveness was especially marked for the mu opioid, morphine, which showed a 30-fold increase in potency. Interestingly the facilitations seen with the lowest doses of the mu and kappa opioids in this model in normal animals were absent after carrageenan. In addition, a very low dose of spinal naloxone caused a small but significant reduction in the C-fibre evoked responses. These results demonstrate that following peripheral inflammation, functional changes develop in both spinal transmission and modulatory systems. Alterations in the antinociceptive potency of opioid agonists occurs, with the mu agonist, morphine, showing the greatest change.

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