Faculty Collaboration Database

Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABA_B receptor in a rat model of bladder pain. Neuropharmacology 2017 Nov;126:1-11

Date

08/22/2017

Pubmed ID

28823612

DOI

10.1016/j.neuropharm.2017.08.023

Scopus ID

2-s2.0-85027890023 (requires institutional sign-in at Scopus site)   7 Citations

Abstract

Therapeutic use of GABA_B receptor agonists for conditions like chronic abdominal pain, overactive bladder (OAB) and gastroesophageal reflux disease (GERD) is severely affected by poor blood-brain barrier permeability and potential side effects. ADX71441 is a novel positive allosteric modulator (PAM) of the GABA_B receptor that has shown encouraging results in pre-clinical models of anxiety, pain, OAB and alcohol addiction. The present study investigates the analgesic effect of ADX71441 to noxious stimulation of the urinary bladder and colon in rats. In female Sprague-Dawley rats, systemic (i.p), but not intrathecal (i.t), administration of ADX71441 produced a dose-dependent decrease in viscero-motor response (VMR) to graded urinary bladder distension (UBD) and colorectal distension (CRD). Additionally, intra-cerebroventricular (i.c.v.) administration of ADX71441 significantly decreased the VMRs to noxious UBD. In electrophysiology experiments, the drug did not attenuate the responses of UBD-sensitive pelvic nerve afferent (PNA) fibers to UBD. In contrast, ADX71441 significantly decreased the responses of UBD-responsive lumbosacral (LS) spinal neurons in spinal intact rats. However, ADX71441 did not attenuate these LS neurons in cervical (C1-C2) spinal transected rats. During cystometrogram (CMG) recordings, ADX71441 (i.p.) significantly decreased the VMR to slow infusion without affecting the number of voiding contraction. These results indicate that ADX71441 modulate bladder nociception via its effect at the supra-spinal sites without affecting the normal bladder motility and micturition reflex in naïve adult rats.

Author List

Kannampalli P, Poli SM, Boléa C, Sengupta JN

Author

Jyoti N. Sengupta PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Abdominal Oblique Muscles
Acetamides
Allosteric Regulation
Analgesics
Animals
Bacterial Proteins
Colon
Female
Injections, Spinal
Neurons
Nociception
Rats, Sprague-Dawley
Receptors, GABA-B
Spinal Cord
Transcription Factors
Triazines
Urinary Bladder
Visceral Pain