Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury

Abstract

Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)+ neurons in the autonomic nuclei and superficial dorsal horn in L6–S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)− and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH+ neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D2-like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH+ neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non-voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH+ cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH+ neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI.

Role of proNGF/p75 signaling in bladder dysfunction after spinal cord injury

“…Indeed, we found that excitatory glutamatergic inputs to the L6/S1 spinal cord are increased with LM11A-31 administration, and also onto TH + cell bodies and fiber projections. These TH + neurons appear to participate in bladder reflex circuitry after SCI, since transneuronal labeling from the bladder wall labeled TH + cells in similar regions to those identified in the current study (30). In addition, 6-hydroxydopamine treatment not only reduced the number of these TH + neurons but also reduced voiding efficiency (30).…”

“…After SCI, many of these fiber projections appeared lost ( Figure 7D), and instead a distinct group of neurons emerged with clear cell soma morphology in the area of the DCM, expressing both p75 and TH. In accordance with these data, modulating dopamine production has recently been shown to influence micturition after SCI (30).…”

“…These TH + neurons appear to participate in bladder reflex circuitry after SCI, since transneuronal labeling from the bladder wall labeled TH + cells in similar regions to those identified in the current study (30). In addition, 6-hydroxydopamine treatment not only reduced the number of these TH + neurons but also reduced voiding efficiency (30). Although the characteristics of these TH + neurons need further study, this suggests that these neurons underlie the emergence of automatic micturition after SCI.…”

Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats

“…A total of 6 µL of PRV‐152 (Bartha strain, 10 9 pfu/mL, courtesy of Dr. Michael A. Lane), encoding for green fluorescent protein (GFP), was injected into the bladder detrusor at three different sites, including the front, and bilateral sides, 2 µL per site, with a 10 µL Hamilton syringe connected with a fine glass tip . Injection sites were immediately sealed with a small drop of tissue glue.…”

Normal Distribution and Plasticity of Serotonin Receptors after Spinal Cord Injury and Their Impacts on Motor Outputs

“…This might be due to that the detecting techniques used in related studies were not sensitive enough to disclose a small amount of 5-HT, or the turnover rate of 5-HT produced in the AADC cells was so high that once produced it was immediately metabolized. One piece of evidence to support the speculation that monoamine transmitters could be produced from AADC cells in the spinal cord after SCI comes from Hou et al [199], who showed that the number of dopamine-producing cells, which contained both AADC and tyrosine hydroxylase, was increased in lumbosacral spinal cord in thoracic spinal transected rats; and with enzyme-linked immunosorbent assay (ELISA) dopamine with a content of about 10% of its normal value could be detected in this part of the spinal cord even without L-dopa applica-tion. At the same time they also showed that dopamine produced from the spinal cord below the lesion was implicated for micturition functional recovery following SCI.…”