Estradiol Treatment Prevents Injury Induced Enhancement in Spinal Cord Dynorphin Expression

Administration of the ovarian steroid estradiol in male and female animals has been shown to have neuromodulatory and neuroprotective effects in a variety of experimental models. In the present study, spinal tissues from dermatomes just above (T5–T7, at level) a severe chronic spinal cord injury (SCI) at T8 were analyzed for expression levels of prodynorphin (PRDN) and phospho-(serine 369) κ-opioid receptor (KOR-P) in 17 β estradiol (EB)- and placebo-treated adult male rats. Dynorphin was targeted since (1) it has previously been shown to be elevated post-SCI, (2) intrathecal injection of dynorphin produces several of the same adverse effects seen with a SCI, and (3) its increased expression is known to occur in a variety of different experimental models of central neuropathic pain. A significant elevation of extracellular levels of both PRDN and KOR-P in the placebo-treated SCI group relative to uninjured surgical sham controls was found in spinal tissues above the injury level, indicating increased dynorphin levels. Importantly, the EB-treated SCI group did not show elevations of PRDN levels at 6 weeks post-injury. Immunohistochemical analysis of at level tissues revealed that EB treatment significantly prevented a post-SCI increase in expression of PRDN puncta co-labeling synapsin I, a nerve terminal marker. The dynorphin-containing terminals co-labeled vesicular glutamate receptor-2 (a marker of glutamatergic terminals), a finding consistent with a non-opioid basis for the adverse effects of dynorphin. These results support a beneficial role for EB treatment post-SCI through a reduction in excessive spinal cord levels of dynorphin. Studies manipulating the timing of the EB treatment post-injury along with specific functional assessments will address whether the beneficial effects are due to EB’s potential neuromodulatory or neuroprotective action

Urinary Bladder Irritation Alters Efficacy of Vagal Stimulation on Rostral Medullary Neurons in Chronic T8 Spinalized Rats

ABSTRACT The presence of pelvic visceral inputs to neurons in the rostral medulla that are responsive to electrical stimulation of the abdominal branches of the vagus nerve (VAG-abd) was investigated in a complete chronic T8 spinal transection rat model. Using extracellular electrophysiological recordings from single medullary reticular formation (MRF) neurons, 371 neurons in 15 rats responsive to pinching the ear (search stimulus) were tested for somato-visceral and viscero-visceral convergent responses to stimulation of the following nerves/territories: VAG-abd, dorsal nerve of the penis, pelvic nerve, distention of urinary bladder and colon, penile stimulation, urethral infusion, and touch/pinch of the entire body surface. In addition to these mechanical and electrical stimuli, a chemical stimulus applied to the bladder was assessed as well. Of the total neurons examined, 205 were tested before and 166 tested beginning 20 min after application of a chemical irritant (2% acetic acid) to the urinary bladder (same rats used pre/post irritation). As with intact controls, many earresponsive MRF neurons responded to the electrical stimulation of VAG-abd. Although MRF neuron responses failed to be evoked with direct (mechanical and electrical nerve) pelvic visceral stimuli, acute chemical irritation of the urinary bladder produced a significant increase in the number of MRF neurons responsive to stimulation of VAG-abd. The results of this study indicate a central effect that potentially relates to some of the generalized below level pelvic visceral sensations that have been documented in patients with complete spinal cord injury

Effects of 17β-Estradiol on Responses of Viscerosomatic Convergent Thalamic Neurons in the Ovariectomized Female Rat

Ovarian hormones have been shown to exert multiple effects on CNS function and viscerosomatic convergent activity. Ovariectomized (OVX) female rats were used in the present study to examine the long-term effects of proestrus levels of 17β-estradiol (EB) delivered by a 60-day time-released subcutaneous pellet on the response properties of viscerosomatic convergent thalamic neurons. In addition, avoidance thresholds to mechanical stimulation for one of the convergent somatic territories, the trunk, was assessed using an electro–von Frey anesthesiometer before and at the end of the 6-wk post-OVX/implant period prior to the terminal electrophysiological experiments, which were done under urethane anesthesia. Rats implanted with an EB-containing pellet, relative to placebo controls, demonstrated 1) altered thalamic response frequencies and thresholds for cervix and vaginal but not colon stimulation; 2) some response variations for just the lateral group of thalamic subnuclei; and 3) altered thalamic response frequencies and thresholds for trunk stimulation. Thalamic response thresholds for trunk pressure in EB versus placebo rats were consistent with the avoidance thresholds obtained from the same groups. In addition, EB replacement affected visceral and somatic thresholds in opposite ways (i.e., reproductive-related structures were less sensitive to pressure, whereas somatic regions showed increased sensitivity). These results have obvious reproductive advantages (i.e., decreased reproductive organ sensitivity for copulation and increased trunk sensitivity for lordosis posturing), as well as possible clinical implications in women suffering from chronic pelvic pain syndromes and/or neuropathic pain