Characterization of opioid receptors that modulate nociceptive neurotransmission in the trigeminocervical complex

Abstract

1 Opioid agonists have been used for many years to treat all forms of headache, including migraine. We sought to characterize opioid receptors involved in craniovascular nociceptive pathways by in vivo microiontophoresis of m-receptor agonists and antagonists onto neurons in the trigeminocervical complex of the cat. 2 Cats were anaesthetized with a-chloralose 60 mg kg 71 , i.p. and 20 mg kg 71 , i.v. supplements after induction and surgical preparation using halothane. Units were identi®ed in the trigeminocervical complex responding to supramaximal electrical stimulation of the superior sagittal sinus, and extracellular recordings of activity made. 3 Seven-or nine-barrelled glass micropipettes incorporating tungsten recording electrodes in their centre barrels were used for microiontophoresis of test substances onto cell bodies. 4 Superior sagittal sinus (SSS)-linked cells whose ®ring was evoked by microiontophoretic application of L-glutamate (n=8 cells) were reversibly inhibited by microiontophoresis of H 2 N-Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO) (n=12), a selective m-receptor agonist, in a dose dependent manner, but not by control ejection of sodium or chloride ions from a barrel containing saline. 5 The inhibition by DAMGO of SSS-linked neurons activated with L-glutamate could be antagonized by microiontophoresis of selective m-receptor antagonists D-Phe-Cys-Tyr-D-Trp-OrnThr-Pen-Thr-NH 2 (CTOP) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), or both, in all cells tested (n=4 and 6, respectively). 6 Local iontophoresis of DAMGO during stimulation of the superior sagittal sinus resulted in a reduction in SSS-evoked activity. This e ect was substantially reversed 10 min after cessation of iontophoresis. The e ect of DAMGO was markedly inhibited by co-iontophoresis of CTAP. 7 Thus, we found that m-receptors modulate nociceptive input to the trigeminocervical complex. Characterizing the sub-types of opioid receptors that in¯uence trigeminovascular nociceptive transmission is an important component to understanding the pharmacology of this synapse, which is pivotal in primary neurovascular headache.

Topiramate Inhibits Trigeminovascular Neurons in the Cat

“…Using electrophysiological methods, neurons within the trigeminocervical complex of the cat responding to a nociceptive stimulus contain two distinct populations of GABA receptors corresponding to the GABA A and GABA B class. Most cells are inhibited by the GABA A agonist muscimol, an effect reversed by the GABA A antagonist N ‐methylbicuculline, but not by the GABA B antagonist 2‐hydroxysaclofen (46). Many fewer units are inhibited by the GABA B agonist baclofen (46).…”

Convergence of cervical and trigeminal sensory afferents

“…Opioid receptors also are involved in cardiovascular nociception, specifically within the trigeminocervical complex. Studies using microiontophoresis determined that -receptor agonists inhibit neurons in the TNC post-synaptic to trigeminal afferents [45]. Valproic acid, an inhibitor of γ aminobutyric acid (GABA) aminotransferase, when applied to the rat in the trigeminocervical nociceptive models, reduced the expression of c-fos-positive cells in the TNC [46] after trigeminal stimulation.…”

“…However, it also receives other inputs that participate in head pain control. The parasympathetic system (vagus nerve), together with the TNC and LCN (trigeminocervical [46]; 5-HT 1 receptors for dihydroergotamine; opioids-receptor [47]; GABA-A-receptors [48,49]; trigeminocervical complex-trigeminal nucleus caudalis and lateral cervical nucleus [10,[15][16][17]23,44,45]; hypoglossal afferents [22]; simpato afferents [20,21]. structures), could increase or decrease the pain signals.…”

Atypical primary headache responding to finger pressure: possible involvement of the vagus nerve?

“…It is feasible that trigeminovascular inhibition plays a role in the antimigraine effect of topiramate, although it is unlikely to be the full explanation for its effects. The effect of topiramate on TCC could play a major role in its antimigrainous activity [10].…”