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

Abstract

Therapeutic use of GABAB 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 GABAB 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.

Authors+Show Affiliations

Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA.Addex Therapeutics, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.Addex Therapeutics, 14 Chemin des Aulx, CH-1228 Plan-les-Ouates, Geneva, Switzerland.Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Pediatric Gastroenterology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: sengupta@mcw.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28823612

Citation

Kannampalli, Pradeep, et al. "Analgesic Effect of ADX71441, a Positive Allosteric Modulator (PAM) of GABAB Receptor in a Rat Model of Bladder Pain." Neuropharmacology, vol. 126, 2017, pp. 1-11.
Kannampalli P, Poli SM, Boléa C, et al. Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain. Neuropharmacology. 2017;126:1-11.
Kannampalli, P., Poli, S. M., Boléa, C., & Sengupta, J. N. (2017). Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain. Neuropharmacology, 126, 1-11. https://doi.org/10.1016/j.neuropharm.2017.08.023
Kannampalli P, et al. Analgesic Effect of ADX71441, a Positive Allosteric Modulator (PAM) of GABAB Receptor in a Rat Model of Bladder Pain. Neuropharmacology. 2017;126:1-11. PubMed PMID: 28823612.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Analgesic effect of ADX71441, a positive allosteric modulator (PAM) of GABAB receptor in a rat model of bladder pain. AU - Kannampalli,Pradeep, AU - Poli,Sonia-Maria, AU - Boléa,Christelle, AU - Sengupta,Jyoti N, Y1 - 2017/08/18/ PY - 2017/03/29/received PY - 2017/07/26/revised PY - 2017/08/16/accepted PY - 2017/8/22/pubmed PY - 2018/6/13/medline PY - 2017/8/22/entrez KW - GABA(B) receptor KW - Interstitial cystitis KW - PAM modulators KW - Painful bladder syndrome KW - Visceral nociception SP - 1 EP - 11 JF - Neuropharmacology JO - Neuropharmacology VL - 126 N2 - Therapeutic use of GABAB 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 GABAB 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. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/28823612/Analgesic_effect_of_ADX71441_a_positive_allosteric_modulator__PAM__of_GABAB_receptor_in_a_rat_model_of_bladder_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0028-3908(17)30390-8 DB - PRIME DP - Unbound Medicine ER -