Activation of 5‐HT_1B/1D receptor in the periaqueductal gray inhibits nociception

Abstract

It is considered that the site of action of the abortive antimigraine compounds acting at serotonin, 5-HT(1B/1D,) receptors (triptans) is the trigeminovascular system. We tested whether there is a non-trigeminal site of action. The 5-HT(1B/1D) agonist, naratriptan, was microinjected into the ventrolateral periaqueductal gray (vlPAG), and activity in the trigeminal nucleus caudalis (TNC) was monitored. Recordings were made from 20 nociceptive neurons in the dorsal horn of the TNC that received convergent input from the dura mater and face. Responses of neurons to dural, facial cutaneous and corneal stimulation were studied before and after injection of naratriptan. Naratriptan decreased the excitability to electrical stimulation of the dura mater as the A-fiber response decreased by 24 +/- 4.1% (p < 0.001) and the C-fiber response decreased by 42 +/- 8.2% (p < 0.001). Spontaneous activity was decreased by 38 +/- 7.5% (p < 0.001). After injection, the mechanical thresholds of the dura mater increased from (n = 14, p < 0.01). Responses to stimulation of the face and cornea were not altered by injection of naratriptan. These results suggest that 5-HT(1B/1D) receptor activation in the vlPAG activates descending pain-modulating pathways that inhibit dural, but not facial and corneal nociceptive input. These findings have implications for the understanding of the action of triptans in migraine and cluster headache, suggesting that brain loci other than the trigeminal nucleus may play a role in the clinical action of triptans.

Tissue Injury Regulates Serotonin 1D Receptor Expression: Implications for the Control of Migraine and Inflammatory Pain

“…Because there are certainly differences in the central consequences of complete transection versus chronic constriction injury, it will be of great interest to determine whether dorsal horn 5-HT 1D -IR is regulated differently in the latter model of neuropathic pain. Together with other reports that triptans are differentially analgesic for pain after activation of trigeminal afferents, we cannot exclude the possibility of a differential regulation of 5-HT 1D receptor in the trigeminal nucleus, or the differential activation of descending nociceptive controls by triptans (Cumberbatch et al, 1998;Bartsch et al, 2004).…”

“…In the periphery, triptans prevent or block neurogenic inflammation (Moskowitz, 1993;Bolay et al, 2002), at least in part, by inhibiting the release of substance P (SP) and CGRP from peptidergic afferents (Buzzi et al, 1991). There is also evidence for a central action of triptans (Kaube et al, 1993;Shepheard et al, 1995), including presynaptic regulation of neurotransmitter release from the central terminals of primary afferents in the trigeminal nucleus caudalis (Jennings et al, 2004;Levy et al, 2004), postsynaptic regulation of the responses of caudalis neurons to glutamate or an NMDA agonist (Goadsby et al, 2001), and activation of triptan receptors expressed by pain-modulatory neurons in the periaqueductal gray (Bartsch et al, 2004).…”

Where do triptans act in the treatment of migraine?

“…The authors acknowledged that this experiment did not exclude the interesting possibility of triptan action on an intrinsic interneuron that modulates the activity of the neuron in question. Perhaps the most direct evidence for multiple CNS sites of triptan action is the report that microinjection of naratriptan into the periaqueductal gray selectively inhibits durally-evoked nociceptive responses of TNC neurons with shared dural and facial receptive fields (Bartsch et al, 2004).…”

Cannabinoid (CB1) Receptor Activation Inhibits Trigeminovascular Neurons

“…The receptive field was assessed for both non-noxious, with gentle brushing, and noxious inputs; the latter was assessed by pinching with forceps or applying heavy pressure that was painful when applied to humans. When a neuron sensitive to stimulation of the ophthalmic dermatome of the trigeminal nerve was identified, it was tested for convergent input from the dura mater (Bartsch et al, 2004). According to the cutaneous receptive field properties, neurons were classified as low-threshold mechanoreceptors that responded only to innocuous stimulation, nociceptivespecific receptors that responded to only noxious input, or widedynamic range that responded to both noxious and non-noxious stimuli (Hu et al, 1981).…”