Dwight Nelson

Neural pathways involved in sacral neuromodulation of reflex bladder activity in cats

This study examined the mechanisms underlying the effects of sacral neuromodulation on reflex bladder activity in chloralose-anesthetized cats. Bladder activity was recorded during cystometrograms (CMGs) or under isovolumetric conditions. An S1-S3 dorsal (DRT) or ventral root (VRT) was electrically stimulated at a range of frequencies (1-30 Hz) and at intensities relative to threshold (0.25-2T) for evoking anal/toe twitches. Stimulation of DRTs but not VRTs at 1T intensity and frequencies of 1-30 Hz inhibited isovolumetric rhythmic bladder contractions. A 5-Hz DRT stimulation during CMGs was optimal for increasing (P < 0.05) bladder capacity (BC), but stimulation at 15 and 30 Hz was ineffective. Stimulation of the S1 DRT was more effective (increases BC to 144% and 164% of control at 1T and 2T, respectively) than S2 DRT stimulation (increases BC to 132% and 150% of control). Bilateral transection of the hypogastric or pudendal nerves did not change the inhibitory effect induced by S1 DRT stimulation. Repeated stimulation of S1 and S2 DRTs during multiple CMGs elicited a significant (P < 0.05) increase in BC (to 155 ± 11% of control) that persisted after termination of the stimulation. These results in cats suggest that the inhibition of reflex bladder activity by sacral neuromodulation occurs primarily in the central nervous system by inhibiting the ascending or descending pathways of the spinobulbospinal micturition reflex.

Comparison of neural targets for neuromodulation of bladder micturition reflex in the rat.

Spinal nerve (SN) stimulation inhibits the bladder rhythmic contraction (BRC) in anesthetized rats. This preparation was used to study the effects of electrical stimulation of the tibial nerve (TN) and the dorsal nerve of the clitoris (DNC) on BRC. Stimulation of the TN and DNC for 10 min produced a frequency- and intensity-dependent attenuation of the frequency of bladder contractions. As observed with the SN, 10-Hz stimulation of either TN or DNC produced the greatest degree of inhibition, with lower or higher frequencies being either less efficacious or inactive. In contrast to the prolonged inhibition produced by SN stimulation, both TN and DNC stimulation produced short lasting inhibition of bladder contractions and the maximal inhibition occurred during stimulation. TN stimulation was effective over only a narrow range of current intensities [3-4 × motor threshold current for inducing a toe twitch (T(mot))] and only at a frequency of 10 Hz. Stimulation of TN at 10 Hz, 3 × T(mot) inhibited BRC to 23% of control. Ten-hertz DNC stimulation at 2 × T(EAS), the threshold current for evoking a reflex anal sphincter contraction, decreased the frequency of contractions to 4% of control. Although compared with the respective threshold current the BRC response was more sensitive to DNC compared with TN stimulation, the absolute current required to reduce BRC using DNC stimulation appeared to be higher. Comparing the effects of TN and DNC stimulation to our previous results with SN stimulation, SN stimulation produces the largest duration and efficacy of bladder inhibition.

Neuromodulation in a rat model of the bladder micturition reflex

A rat model of bladder reflex contraction (BRC) was used to determine the optimal frequency and intensity of spinal nerve (SN) stimulation to produce neuromodulation of bladder activity and to assess the therapeutic mechanisms of this neuromodulation. In anesthetized female rats (urethane 1.2 g/kg ip), a wire electrode was used to produce bilateral stimulation of the L6 SN. A cannula was placed into the bladder via the urethra, and the urethra was ligated to ensure an isovolumetric bladder. Saline infusion induced BRC. Electrical stimulation of the SN produced a frequency- and intensity-dependent attenuation of the frequency of bladder contractions. Ten-herz stimulation produced maximal inhibition; lower and higher stimulation frequency produced less attenuation of BRC. Attenuation of bladder contraction frequency was directly proportional to the current intensity. At 10 Hz, stimulation using motor threshold pulses (T(mot)) produced a delayed inhibition of the frequency of bladder contractions to 34 ± 11% of control. Maximal bladder inhibition appeared at 10 min poststimulation. High current intensity at 0.6 mA (∼6 * T(mot)) abolished bladder contraction during stimulation, and the inhibition was sustained for 10 min poststimulation (prolonged inhibition). Furthermore, in rats pretreated with capsaicin (125 mg/kg sc), stimulation produced a stronger inhibition of BRC. The inhibitory effects on bladder contraction may be mediated by both afferent and efferent mechanisms. Lower intensities of stimulation may activate large, fast-conducting fibers and actions through the afferent limb of the micturition reflex arc in SN neuromodulation. Higher intensities may additionally act through the efferent limb.

Role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve stimulation

The role of the endogenous opioid system in modulation of urinary bladder activity by spinal nerve (SN) stimulation was studied in anesthetized female rats, using the rat model of isovolumetric bladder contraction. SN stimulation at a fixed frequency of 10 Hz attenuated bladder contraction frequency; the magnitude of the inhibition was directly proportional to the current intensity. Neither the κ-opioid antagonist nor-binaltorphimine (2 mg/kg iv) nor the δ-opioid antagonist naltrindole (5 mg/kg iv) attenuated the bladder inhibitory response to SN stimulation. In contrast, the μ-opioid receptor antagonist naloxone (NLX; 0.03 mg/kg iv) blocked the inhibitory responses evoked by SN stimulation at therapeutic current intensities at ≤1 × motor threshold current (Tmot). An action at spinal and supraspinal centers was further confirmed by the ability of intrathecal or intracerebroventricular administration of NLX methiodide to attenuate the bladder inhibitory effects of 1 × Tmot SN stimulation. The magnitude of SN-mediated neuromodulation using therapeutically relevant stimulation intensity (Tmot) is equivalent to 0.16 mg/kg of systemically administered morphine, which produces 50% inhibition of bladder contraction frequency. These results suggest that the inhibitory effects of lower intensity SN stimulation may be mediated through the release of endogenous μ-opioid peptides. Additionally, these data suggest that neuromodulation may offer a mode of treating the symptoms of overactive bladder with efficacy equal to the opioid drugs but without their liability for abuse and dependence.