Sensitization of meningeal nociceptors: inhibition by naproxen

Abstract

Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non-selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non-selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single-unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non-selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of Aδ-and Cunits and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX-2 inhibitor N- [2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) onto the dural receptive field of Aδ-and C-unit nociceptors also reversed the neuronal hyper-responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache.

Neurophysiological markers of central sensitisation in the trigeminal pathway and their modulation by the cyclo-oxygenase inhibitor ketorolac

“…Taking into account that development of migraine involves aseptic inflammation of meningeal blood vessels and release of prostaglandins, the use of such drugs for stopping headache attacks seems pathogenetically justified (17). Moreover, our data in conjunction with previous reports (6,10,17), indicate that, in addition to peripheral anti-inflamatory effects, ketorolac and other NSAIDs have a direct analgesic action which is unlikely to be only at the level of peripheral afferent endings of the trigeminal nerve. Our data suggest that the mechanisms of ketorolac action involve reversal of hyperexcitability of spinal trigeminal neurons which, in turn, will result in inhibition of nociceptive traffic to the higher nervous structures and in decrease (normalisation) of peripheral sensitivity.…”

Identification of Cytokines and Signaling Proteins Differentially Regulated by Sumatriptan/Naproxen

“…On the other hand, naproxen is proposed to function as a migraine therapy by inhibiting the synthesis and release of prostaglandins from mast cells. 40, 41 However, a somewhat surprising finding from our study was the large number of capsaicin stimulated cytokines and signaling proteins in trigeminal ganglia and spinal trigeminal nucleus that were negatively regulated by naproxen. Interestingly, there is emerging evidence of a co-regulatory loop in which prostaglandins can increase the synthesis of cytokines, and cytokines can also upregulate prostaglandin expression.…”

Naproxen Effects on Brain Response to Painful Pressure Stimulation in Patients with Knee Osteoarthritis: A Double-blind, Randomized, Placebo-controlled, Single-dose Study

“…NSAID compounds such as naproxen have a general antiinflammatory action mainly through cyclooxygenase inhibition, thereby preventing the conversion of arachidonic acid to prostaglandins 27,28 . Naproxen may thus produce analgesia by reducing the nociceptive inputs to brain as a result of its local/peripheral antiinflammatory effect 29,30,31 . On the other hand, reduction of peripheral inflammation may secondarily abort the subsequent central sensitization phenomenon 28 .…”