Systemic and intrathecal baclofen produce bladder antinociception in rats

Abstract

Background: Baclofen, a clinically available GABA_B receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception.

Methods: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity.

Results: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABA_B receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABA_B activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed.

Conclusions: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

Keywords: Antinociception; GABAB receptors; Interstitial cystitis/bladder pain syndrome; Urinary bladder.

Fig. 1

Cumulative dosing of IT baclofen. a Abdominal EMG responses to graded UBD (10–60 mmHg) were quantified as a mean Area-Under-the-Curve (AUC) for each dose of baclofen tested (n = 8; cumulative doses values of 0, 10, 20, 40, 80 and 160 ng) and presented on a log scale. These responses were significantly different for AUC measures in IT saline-treated rats (n = 8). * indicates p < 0.05 for post hoc comparisons. b Stimulus–response functions for the IT baclofen used to generate the AUC data in panel A and Table 1. c Individual example of rectified electromyographic activity in a single rat before and after stated doses of IT baclofen

Fig. 2

Time course of IT baclofen effect on reflex responses to UBD. Graphs depict the rapid onset and duration of inhibitory effect of a single 40 ng dose of IT baclofen or IT normal saline on repeated pressor (A) and viscero-motor (B) responses evoked by a urinary bladder distension (60 mm Hg, 20 s, every 3 min) normalized as percentage of pre-drug responses. N = 6/group

Fig. 3

Time course of IT baclofen effect on spinal dorsal horn neuronal responses to UBD. Graph depict the rapid onset and duration of a single 160 ng dose of IT baclofen or IT normal saline applied topically to the dorsal surface of the spinal cord on repeated neuronal responses to urinary bladder distension (60 mm Hg, 20 s, every 3 min) normalized as percentage of pre-drug responses. See text for more complete description. N = 10/group. *, **p < 0.05 and p < 0.01 respectively for post hoc comparisons with IT saline-treated rats