The 5-HT(4) receptor agonist
tegaserod (TEG) has been reported to modulate
visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the
analgesic mechanism and site of action of TEG. In male rats,
visceral pain was assessed by measuring visceromotor response (VMR) to colorectal distension (CRD).
Inflammation was induced by intracolonic injection of tri-
nitrobenzene sulfonic acid (TNBS). The effect of TEG on the VMR was tested by injecting intraperitoneal (i.p.), intrathecal (i.t.), intracerebroventricular (i.c.v) or in the rostroventral medulla (RVM). The effect of the
drug was also tested on responses of CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons. Systemic injection of TEG attenuated VMR in naive and TNBS-treated rats. Similarly, supraspinal, but not
spinal, injection of TEG attenuated the VMR. While
GR113808, (selective 5-HT(4) antagonist) blocked the effect,
naloxone (NLX) an
opioid receptor antagonist reversed the effect of TEG. Although i.t. NLX did not block the inhibitory effect of TEG in VMR study, i.t. injection of α2-adrenergic receptor antagonist
yohimbine blocked the effect of TEG when given systemically. While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by
GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces
analgesia via activation of supraspinal 5-HT(4) receptors which triggers the release of
opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce
analgesia.