NSAID-induced cyclooxygenase inhibition differentially depresses long-lasting versus brief synaptically-elicited responses of rat spinal dorsal horn neurons in vivo

Abstract

This electrophysiological study examined the effects of NSAID administration on synaptically-elicited responses of rat single spinal dorsal horn neurons to natural stimulation of peripheral receptive fields. Nociceptive responses consisted of a fast initial discharge during the stimulus followed by a slowly-decaying afterdischarge. The cyclooxygenase inhibitor, indomethacin (2.0–8.0 mg/kg, i.v.), was without effect on the on-going rate of discharge but dose-dependently inhibited synaptically-elicited responses to noxious cutaneous mechanical stimulation (fast initial discharge: n=3/3 with 2 mg/kg, 5/8 with 4 mg/kg, 5/6 with 8 mg/kg; slowly-decaying afterdischarge: n=3/3 with 2 mg/kg, 6/8 with 4 mg/kg, 6/6 with 8 mg/kg) and thermal (fast initial discharge: n=7/9 with 8 mg/kg; slowly-decaying afterdischarge: n=3/4 with 4 mg/kg, n=7/9 with 8 mg/kg). The inhibitory effect of indomethacin started within 2–4 min and lasted up to 120 min. To eliminate any effect of indomethacin via cutaneous sensory receptors it was tested on the responses of some neurons to high intensity electrical stimulation of the sciatic nerve; indomethacin depressed these evoked responses (fast initial discharge: n=5/6 with 2 mg/kg, n=7/7 with 4 mg/kg; slowly-decaying afterdischarge: n=6/6 with 2 mg/kg, n=7/7 with 4 mg/kg). The brief excitatory responses to innocuous pressure (fast initial discharge: n=2/3 with 2 mg/kg, n=6/8 with 4 mg/kg, n=4/6 with 8 mg/kg) and hair (n=2/7 with 2 and 4 mg/kg, respectively) stimulation in both non-nociceptive and wide dynamic range neurons were also depressed but to a lesser extent. However, the prolonged excitation of three wide dynamic range neurons to continuous hair stimulation was almost entirely inhibited by indomethacin. Overall, inhibition of the afterdischarge and the excitatory effect of long-lasting synaptic input were greater than inhibition of the fast synaptic input-evoked initial discharge. The evidence supports the suggestion that systemically-administered indomethacin has an effect in the spinal cord and demonstrates an action specifically in the dorsal horn. The data are interpreted to suggest that sensory inputs are more involved than input-independent excitation of dorsal horn neurons in leading to de novo synthesis of eicosanoids and that the time course of this synthesis brings the levels to a point where COX inhibition can have an observable effect during prolonged excitation. Although the data suggest that COX inhibition differentially inhibits nociceptive versus non-nociceptive mechanisms at the cellular level, irrespective of the modality of the stimulus, this is the first direct demonstration that prolonged activation of synaptic mechanisms are preferentially inhibited. According to this it would be predictable that NSAIDs would be more effective on nociceptive types of pain characterized by time or prolonged inputs of primary afferents.