Sensitization of central trigeminovascular neurons: blockade by intravenous naproxen infusion

Abstract

We have previously observed that migraine attacks impervious to triptan therapy were readily terminated by subsequent i.v. administration of the non-steroidal anti-inflammatory drug (NSAID) ketorolac. Since such attacks were associated with periorbital allodynia--a symptom of central sensitization--we examined whether infusion of the NSAID naproxen can block sensitization of central trigeminovascular neurons in the medullary dorsal horn, using in vivo single-unit recording in the rat. Topical exposure of the cerebral dura to inflammatory soup (IS) for 5 min resulted in a short-term burst of activity (<8 min) and a long-lasting (>120 min) neuronal hyper-responsiveness to stimulation of the dura and periorbital skin (group 1). Infusion of naproxen (1 mg/kg) 2 h after IS (group 1) brought all measures of neuronal responsiveness back to the baseline values recorded prior to IS, and depressed ongoing spontaneous activity well below baseline. When given preemptively 1 h before IS (group 2), naproxen blocked the short-term burst of activity and every long-term measure of neuronal hyper-responsiveness that was studied in the central neurons. The same preemptive treatment, however, failed to block IS-induced short-term bursts of activity in C-unit meningeal nociceptors (group 3). The results suggest that parenteral administration of naproxen, unlike triptan therapy, can exert direct inhibition over central trigeminovascular neurons in the dorsal horn. Though impractical as a routine migraine therapy, parenteral NSAID administration should be useful as a non-narcotic rescue therapy for migraine in the setting of the emergency department.

Fig. 1

Experimental design. Group 1 examined whether naproxen infusion terminates ongoing sensitization that was induced earlier by a 5-min exposure of the dura to IS. Group 2 examined whether naproxen infusion prevents activation and induction of sensitization by subsequent exposure of the dura to IS. Green – baseline; red – after IS; Blue – after naproxen.

Fig. 2

Recording sites and receptive fields – group 1. (A) Lesions marking individual recording sites in the spinal trigeminal nucleus and the respective neuronal receptive fields in the dura and facial skin. (B) an example of expansion and contraction of dural and cutaneous receptive fields in response to IS and naproxen, respectively. Green – baseline; red – after IS; Blue – after naproxen. Numbers identify individual rats.

Fig. 3

Effects of naproxen infusion on responsiveness of sensitized central trigeminovascular neurons to stimulation of their cutaneous receptive field – group 1. Shown are examples of responses to brush and pressure (A) and heat (B) in a neuron studied before (baseline/green) and after IS (red), and again after naproxen infusion (blue). Bin width: 0.5 sec. Numbers in parentheses indicate mean spikes/sec during the pre-stimulus intervals and during the response intervals. Notice that the magnitude of all responses decreased below baseline values, and that heat response threshold returned to baseline after naproxen infusion.

Fig. 4

Summary of the effects of naproxen infusion on responsiveness of sensitized central trigeminovascular neurons to skin stimulation – group 1. Shown are mean±SEM response magnitude to brush (A) and pressure (B), and response threshold to heat (C) before (baseline/green) and after IS (red), and again after naproxen infusion (blue). Gray bars (A, B) indicate spontaneous activity in the 10-sec interval that preceded the stimulus. Probability values indicate significant overall differences across green, red and blue bars (Friedman test). ^ap<0.02 and ^bp<0.03 vs. respective green bars; ^cp<0.02 vs. respective red bars (Wilcoxon test).

Fig. 5

Effects of naproxen infusion on spontaneous activity of sensitized central trigeminovascular neurons – group 1. (A) mean firing rate of a single neuron studied before (baseline/green) and after IS (red), and again after naproxen infusion (blue). Bin width: 1 sec; numbers in parentheses indicate mean spikes/sec during the entire 600-msec intervals. (B) mean±SEM firing rate of all neurons (color coded as above). Significant overall differences across green, blue and red bars (p<0.003, Friedman test). ^ap<0.01 vs. green bar; ^bp<0.01 vs. red bar (Wilcoxon test). Notice that ongoing firing rate was suppressed below baseline values after naproxen infusion.

Fig. 6

Recording sites and receptive fields – group 2. (A) Lesions marking individual recording sites in the spinal trigeminal nucleus and the respective neuronal receptive fields in the dura and facial skin. (B) an example of contraction of dural and cutaneous receptive fields in response to naproxen, and failure of IS to induce expansion of the receptive fields. Green – baseline; blue – after naproxen; red – after IS;. Numbers identify individual rats.

Fig. 7

Effects of naproxen infusion on responsiveness of non-sensitized central trigeminovascular neurons to stimulation of their cutaneous receptive field – group 2. Shown are examples of responses to brush and pressure (A) and heat (B) in a neuron studied before (baseline/green) and after naproxen infusion (blue), and again after IS (red). Bin width: 0.5 sec. Numbers in parentheses indicate mean spikes/sec during the pre-stimulus intervals and during the response intervals. Notice that naproxen infusion markedly suppressed the magnitude of all responses below baseline values, shifted heat response threshold above baseline, and blocked induction of hyper-responsiveness by IS.

Fig. 8

Summary of the effects of naproxen infusion on responsiveness of non-sensitized central trigeminovascular neurons to skin stimulation – group 2. Shown are mean±SEM response magnitude to brush (A) and pressure (B), and response threshold to heat (C) before (baseline/green) and after naproxen infusion (blue), and again after IS (red). Gray bars (A, B) indicate spontaneous activity in the 10-sec interval that preceded the stimulus. Probability values indicate significant overall differences across green, blue and red bars (Friedman test). ^ap<0.02 and ^bp<0.05 vs. respective green bars; ^cp<0.05 vs. respective blue bar (Wilcoxon test).

Fig. 9

Effects of naproxen infusion on spontaneous activity of non-sensitized central trigeminovascular neurons – group 2. (A) mean firing rate of a single neuron studied before (baseline/green) and after IS (red), and again after naproxen infusion (blue). Bin width: 1 sec; numbers in parentheses indicate mean spikes/sec during the entire 600-msec intervals. (B) mean±SEM firing rate of all neurons (color coded as above). Notice that naproxen infusion markedly suppressed ongoing firing rate below baseline values. Significant overall differences across green, blue and red bars (p<0.004, Friedman test). ^ap<0.03 vs. green bar; ^bp<0.05 vs. blue bar (Wilcoxon test).

Fig. 10

Naproxen inhibition of acute response to IS in a central trigeminovascular neuron. Shown are examples of IS-induced increase in mean firing rate of a naïve neuron (A) and the suppression of IS-induced discharge in a neuron previously exposed to naproxen infusion (B). Green – baseline; blue – after naproxen; red – after IS. Bin width: 1 sec. Numbers in parentheses indicate mean spikes/sec during the pre-stimulus intervals and during the response intervals. Exposure of the dura to IS for 5 min is indicated by black line.

Fig. 11

Example of an acute response to IS in a C-unit meningeal nociceptor previously exposed to naproxen infusion. Blue – after naproxen and before IS; red – after IS. Bin width: 0.5 sec.