CP‐93,129, sumatriptan, dihydroergotamine block c‐fos expression within rat trigeminal nucleus caudalis caused by chemical stimulation of the meninges
Authors: Nozaki Kazuhiko , Moskowitz Michael A. , Boccalini Pia 
Published: July 2012

The effects of intravenously administered 5‐HT1B receptor agonists were examined on c‐fos‐like immunoreactivity, an indicator of neuronal activation, within the brain stem. C‐fos was induced by injecting an algesic, vasoconstrictor substance (0.3 ml of autologous blood) or a pro‐inflammatory molecule, carrageenin (1 mg in 0.1 ml saline) into the cisterna magna of pentobarbitone‐anaesthetized Sprague‐Dawley rats and was visualized in serial sections (50 μm) by use of a polyclonal antiserum.

As previously reported, the injection of blood caused significant labelling within laminae I, IIo of the trigeminal nucleus caudalis, a major nociceptive brain stem nucleus, as well as within nucleus of the solitary tract and area postrema. A similar pattern of expression with fewer cells per section was detected after carrageenin instillation. The number of expressing cells was reduced by 54% in trigeminal nucleus caudalis but not within the nucleus of the solitary tract or area postrema when blood was injected in adult rats after neonatal capsaicin treatment.

Pretreatment with 5‐HT1 agonists with some selectivity for the 5‐HT1B receptor, CP‐93,129 (460 nmol kg−1 × 2, i.v.), sumatriptan (720 nmol kg−1 × 2, i.v.) or dihydroergotamine (86 nmol kg−1 × 2, i.v.) reduced positive cells by 39%, 31%, and 33% respectively in trigeminal nucleus caudalis but not in nucleus of the solitary tract or area postrema after blood instillation. Pretreatment with the analgesic morphine (15 μmol kg−1, s.c.) also decreased the number of positive cells by 63% in trigeminal nucleus caudalis.

CP‐93,129 (460 nmol kg−1 × 2, i.v.) reduced the number of c‐fos labelled cells by 47% within lamina I, IIo after carrageenin instillation.

Drug‐induced blockade appeared to be tissue‐dependent. Pretreatment with sumatriptan (720 nmol kg−1 × 2, i.v.) did not block c‐fos expression in trigeminal nucleus caudalis following formalin application to the nasal mucosa.

Drug‐induced blockade may be mediated by an action on primary afferent (trigeminovascular) fibres in as much as CP‐93,129 (460 nmol kg−1 × 2, i.v.) did not reduce the number of expressing cells within the trigeminal nucleus caudalis following blood instillation in rats treated as neonates with capsaicin.

We infer from these results that the analgesic actions of agonists at 5‐HT1B receptors (the receptor subtype analogous to 5‐HT1D in man) need not depend upon the presence of vasodilatation and, that 5‐HT1D receptor‐mediated blockade of neurotransmission contributes significantly to the analgesic effects of these drugs in headache.

Based on the demonstrated effects of 5‐HT1B/d agonists against the actions of two chemically‐unrelated meningeal stimulants, we suggest that treatment with 5‐HT1D agonists may be useful for the alleviation of pain in other headache conditions associated with meningeal irritation. Bacterial, viral (including AIDS meningovascular inflammation) and other forms of chemical meningitis merit further investigation.