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. 2014 Feb 28;20(8):2091-7.
doi: 10.3748/wjg.v20.i8.2091.

ZD 7288, an HCN channel blocker, attenuates chronic visceral pain in irritable bowel syndrome-like rats

Yu Chen  1 , Chun Lin  1 , Ying Tang  1 , Ai-Qin Chen  1 , Cui-Ying Liu  1 , Da-Li Lu  1
Affiliations

ZD 7288, an HCN channel blocker, attenuates chronic visceral pain in irritable bowel syndrome-like rats

Yu Chen et al. World J Gastroenterol. .

Abstract

Aim: To investigate the effects of ZD 7288, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, on rats with chronic visceral pain.

Methods: Rats with visceral hypersensitivity were generated using neonatal colon irritation during postnatal days 8-15 as described previously. Visceral hypersensitivity was evaluated using electromyographic (EMG) responses of abdominal external oblique muscles to 20-80 mmHg colorectal distentions (CRD). Abdominal withdrawal reflex (AWR) scores and pain thresholds were also detected in adult rats. Different doses of ZD 7288 (25, 50, and 100 nmol/L) were intrathecally administered in rats to study the role of spinal HCN channel in chronic visceral hypersensitivity.

Results: EMG responses to 20-80 mmHg CRD and AWR scores under 20-60 mmHg CRD significantly increased in rats with visceral hypersensitivity compared to control rats (P < 0.05). The pain threshold in rats with visceral hypersensitivity significantly decreased compared to control rats (P < 0.05). Treatment with 50-100 nmol/L ZD 7288 significantly inhibited EMG responses (16%-62%, 80-20 mmHg CRD, P < 0.05) and AWR scores (24%-37%, 40-20 mmHg CRD, P < 0.05; 12%-61%, 80-20 mmHg CRD, P < 0.05, respectively), and significantly increased pain thresholds (32%-77%, P < 0.05).

Conclusion: Spinal HCN channels may play an important role in chronic visceral hypersensitivity.

Keywords: Abdominal withdrawal reflex; Electromyography; Hyperpolarization-activated cyclic nucleotide-gated channel; Irritable bowel syndrome; Visceral hypersensitivity; ZD 7288.

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Figures

Figure 1
Figure 1
Behavioral evaluation of visceral pain. A: Schematic drawings illustrating the visually based behavioral scale of the abdominal withdrawal reflex (AWR) in response to graded colorectal distension (CRD). AWR scores are 0, 1, 2, 3, and 4; B: AWR scores of control and irritable bowel syndrome (IBS)-like rats; C: Pain thresholds measured by AWR in rats. The AWR threshold indicates CRD intensity when the AWR score is 3. aP < 0.05 compared with control rats.
Figure 2
Figure 2
Electromyographic responses to colorectal distension in rats. The average responses to graded colorectal distension (CRD) were significantly increased in irritable bowel syndrome (IBS)-like rats compared with control rats. bP < 0.01, compared with control rats at the same CRD intensity. EOMA: External oblique muscle of the abdomen.
Figure 3
Figure 3
Inhibitory effects of ZD 7288 on amplitudes of external oblique muscle of the abdomen in irritable bowel syndrome-like rats. aP < 0.05, compared with saline-treated irritable bowel syndrome (IBS)-like rats; dP < 0.01, compared with IBS-like rats receiving 50 nmol/L ZD 7288. EOMA: External oblique muscle of the abdomen; CRD: colorectal distension.
Figure 4
Figure 4
Inhibitory effects of ZD 7288 on abdominal withdrawal reflex scores (A) and pain thresholds (B) of irritable bowel syndrome-like rats. aP < 0.05, compared with saline-treated IBS-like rats; dP < 0.01, compared with IBS-like rats receiving 50 nmol/L ZD 7288. CRD: Colorectal distension; AWR: Abdominal withdrawal reflex.
Figure 5
Figure 5
Effects of ZD 7288 on amplitudes of external oblique muscle of the abdomen in control rats. EOMA: External oblique muscle of the abdomen; CRD: Colorectal distension.
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