Dual role of 5-HT3 receptors in a rat model of delayed stress-induced visceral hyperalgesia.
Despite its beneficial effect in IBS patients, the mechanism of action of the 5-HT3 receptor (5-HT3R) antagonist alosetron is still incompletely understood. We aimed to characterize the effect and site(s) of action in a model of stress-induced sensitization of visceral nociception in rats. Adult male Wistar rats were equipped for recording of visceromotor response (VMR) to phasic colorectal distension (CRD; 10-60 mmHg). VMR to CRD was recorded 24 h after an acute session of water avoidance (WA) stress (post-WA). Baseline and post-WA responses were measured in rats exposed to WA or sham-WA, treated with alosetron at 0.3 mg/kg subcutaneously (s.c.) 25 nmol intrathecally (i.t.) or vehicle before post-WA CRD. Some rats were treated with capsaicin/vehicle on the cervical vagus nerve and received alosetron (0.3 mg/kg, s.c.) 15 min before post-WA CRD. WA stress led to visceral hyperalgesia 24 h later. Alosetron (0.3 mg/kg, s.c.), failed to inhibit WA-induced exacerbation of VMR to CRD. Stress-induced visceral hyperalgesia was abolished when alosetron was injected intrathecally (P<0.05) in intact rats or subcutaneously (0.3 mg/kg) in capsaicin-pretreated animals (P<0.05). Capsaicin-pretreatment did not affect the exacerbating effect of stress on visceral sensitivity. Alosetron had no inhibitory effect on normal visceral pain responses when administered subcutaneously or intrathecally. We demonstrated that 5-HT3Rs on central terminals of spinal afferents are engaged in the facilitatory effect of stress on visceral sensory information processing. In addition, we showed that stress-induced sensitization of visceral nociception is independent of 5-HT3R activation on vagal afferents.
Bradesi
Sylvie
S
Center for Neurovisceral Sciences and Women's Health, Department of Medicine, VAGLAHS CURE Building 115, Room 223, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA.
Lao
Lijun
L
McLean
Peter G
PG
Winchester
Wendy J
WJ
Lee
Kevin
K
Hicks
Gareth A
GA
Mayer
Emeran A
EA
D000208:Acute Disease; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D001362:Avoidance Learning; D002211:Capsaicin / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002404:Catheterization; D003106:Colon / Q000294:innervation / Q000502:physiology; D004576:Electromyography; D005765:Gastrointestinal Agents / Q000494:pharmacology; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D043183:Irritable Bowel Syndrome / Q000503:physiopathology; D008297:Male; D009619:Nociceptors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology*; D012007:Rectum / Q000294:innervation / Q000502:physiology; D013315:Stress, Psychological / Q000503:physiopathology*; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology; D017833:Visceral Afferents / Q000502:physiology
D018712:Analgesics, Non-Narcotic; D002243:Carbolines; D005765:Gastrointestinal Agents; D044406:Receptors, Serotonin, 5-HT3; C090840:alosetron; D002211:Capsaicin