Meredith T. Robbins

Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats.

This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague-Dawley (SD; low/moderate anxiety) or Wistar-Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

Effects of Oxytocin and Prolactin on Stress-Induced Bladder Hypersensitivity in Female Rats

UNLABELLED Anecdotal evidence suggests that chronic bladder pain improves while breastfeeding. The present study sought to identify potential mechanisms for such a phenomenon by investigating the effects of the lactogenic hormones prolactin (PL) and oxytocin (OXY) in a rat model of bladder nociception. Lactating rats were less sensitive to urinary bladder distension (UBD) than controls. In investigating potential antinociceptive and anxiolytic roles for these hormones, we found exposure to a footshock paradigm (STRESS groups) produced bladder hypersensitivity in saline-treated rats, manifested as significantly higher electromyographical (EMG) responses to UBD, compared to rats exposed to a nonfootshock paradigm (SHAM groups). This hypersensitivity was attenuated by the intraperitoneal administration of OXY prior to footshock in the STRESS-OXY group. The administration of PL augmented EMG responses in the SHAM-PL group but had no effect on the responses of the STRESS-PL group. In the absence of behavioral pretreatment, OXY attenuated UBD-evoked responses while PL had no effect. Moreover, OXY-treated rats spent more time in the open arm of an elevated plus maze compared to saline-treated rats suggesting anxiolysis. These studies suggest the potential for systemic OXY, but not PL, as an analgesic and anxiolytic treatment for painful bladder disorders such as interstitial cystitis. PERSPECTIVE This study presents evidence that systemic oxytocin has both analgesic and anxiolytic properties which may make it a potentially useful agent for patients with stress-exacerbated chronic-pain syndromes such as interstitial cystitis. These studies do not suggest a similar role for prolactin.

Sex differences in experimental measures of pain sensitivity and endogenous pain inhibition

It has been suggested that increased pain sensitivity and disruption of endogenous pain inhibitory processes may account, at least in part, for the greater prevalence and severity of chronic pain in women compared to men. However, previous studies addressing this topic have produced mixed findings. This study examined sex differences in pain sensitivity and inhibition using quantitative sensory testing (QST), while also considering the influence of other important factors such as depressive symptoms and sleep quality. Healthy men (n=24) and women (n=24) each completed a QST battery. This battery included an ischemic pain task (IPT) that used a submaximal effort tourniquet procedure as well as a conditioned pain modulation (CPM) procedure for the assessment of endogenous pain inhibition. Prior to QST, participants completed the Center for Epidemiologic Studies Depression Scale and the Pittsburgh Sleep Quality Index. Analyses revealed significant sex differences for the ischemic pain task and the conditioned pain modulation procedure, such that women tolerated the ischemic pain for a shorter amount of time and demonstrated less pain inhibition compared with men. This remained true even when accounting for sex differences in depressive symptoms and sleep quality. The results of this study suggest that women may be more pain sensitive and possess less-efficient endogenous pain inhibitory capacity compared with men. Whether interventions that decrease pain sensitivity and enhance pain inhibition in women ultimately improve their clinical pain outcomes is an area of research that deserves additional attention in the future.

Neonatal Bladder Inflammation Produces Functional Changes and Alters Neuropeptide Content in Bladders of Adult Female Rats

UNLABELLED Neonatal bladder inflammation has been demonstrated to produce hypersensitivity to bladder re-inflammation as an adult. The purpose of this study was to investigate the effects of neonatal urinary bladder inflammation on adult bladder function and structure. Female Sprague-Dawley rats were treated on postnatal days 14 to 16 with intravesical zymosan or anesthesia alone. At 12 to 16 weeks of age, micturition frequency and cystometrograms were measured. Similarly treated rats had their bladders removed for measurement of plasma extravasation after intravesical mustard oil, for neuropeptide analysis (calcitonin gene-related peptide or Substance P) or for detailed histological examination. Rats treated with zymosan as neonates exhibited increased micturition frequency, reduced micturition volume thresholds, greater extravasation of Evans blue after intravesical mustard oil administration, and greater total bladder content of calcitonin gene-related peptide and Substance P. In contrast, there were no quantitative histological changes in the thickness, fibrosis, or mast cells of bladder tissue due to neonatal zymosan treatments. Functional changes in urologic systems observed in adulthood, coupled with the increased neuropeptide content and neurogenic plasma extravasation in adult bladders, suggest that the neonatal bladder inflammation treatment enhanced the number, function, and/or neurochemical content of primary afferent neurons. These data support the hypothesis that insults to the urologic system in infancy may contribute to the development of adult bladder hypersensitivity. PERSPECTIVE Inflammation of the bladder early in life in the rat has multiple sequelae, including laboratory measures that suggest an alteration of the neurophysiological substrates related to the bladder. Some painful bladder syndromes in humans have similar characteristics and so may be due to similar mechanisms.

Visceral nociceptive input to the area of the medullary lateral reticular nucleus ascends in the lateral spinal cord

In halothane-anesthetized rats, neurons stereotaxically located in the region of the medullary lateral reticular nucleus (LRN) and responsive to urinary bladder distension (UBD) were characterized using extracellular electrodes. Most neurons excited by UBD were also excited by noxious stimuli applied to bilateral receptive fields comprising at least half of the body surface. These bilateral nociceptive specific (bNS) neurons exhibited graded responses to graded intensities of UBD. Neuronal responses to noxious UBD were highly positively correlated with responses to noxious colorectal distension, suggesting a convergence of visceral sensory information in the area of LRN. Bilateral lateral mid-cervical spinal cord lesions virtually abolished activity of bNS neurons evoked by noxious UBD, while dorsal midline lesions had no significant effect. These data support a role for neurons in the region of the LRN in visceral nociception and implicate traditional lateral spinal cord pain pathways in the transmission of visceral information to caudal ventrolateral medullary structures.

Intranasal Oxytocin Administration is Associated with Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States.

Objectives:This study examined whether the administration of intranasal oxytocin was associated with pain sensitivity, endogenous pain inhibitory capacity, and negative mood states. Materials and Methods:A total of 30 pain-free, young adults each completed 3 laboratory sessions on consecutive days. The first session (baseline) assessed ischemic pain sensitivity, endogenous pain inhibition via conditioned pain modulation (CPM), and negative mood using the Profile of Mood States. CPM was tested on the dominant forearm and ipsilateral masseter muscle using algometry (test stimulus) and the cold pressor task (conditioning stimulus; nondominant hand). For the second and third sessions, participants initially completed the State-Trait Anxiety Inventory and then self-administered a single (40 IU/1 mL) dose of intranasal oxytocin or placebo in a randomized counterbalanced order. Thirty minutes postadministration, participants again completed the State-Trait Anxiety Inventory and repeated assessments of ischemic pain sensitivity and CPM followed by the Profile of Mood States. Results:Findings demonstrated that ischemic pain sensitivity did not significantly differ across the 3 study sessions. CPM at the masseter, but not the forearm, was significantly greater following administration of oxytocin compared to placebo. Negative mood was also significantly lower following administration of oxytocin compared to placebo. Similarly, anxiety significantly decreased following administration of oxytocin but not placebo. Discussion:This study incorporated a placebo-controlled, double-blind, within-subjects crossover design with randomized administration of intranasal oxytocin and placebo. The data suggest that the administration of intranasal oxytocin may augment endogenous pain inhibitory capacity and reduce negative mood states including anxiety.

Oxytocin – A Multifunctional Analgesic for Chronic Deep Tissue Pain

The treatment of chronic pain arising from deep tissues is currently inadequate and there is need for new pharmacological agents to provide analgesia. The endogenous paracrine hormone/neurotransmitter oxytocin is intimately involved in the modulation of multiple physiological and psychological functions. Recent experiments have given clear evidence for a role of oxytocin in the modulation of nociception. The present article reviews the existent human and basic science data related to the direct and indirect effects of oxytocin on pain. Due to its analgesic, anxiolytic, antidepressant and other central nervous system effects, there is strong evidence that oxytocin and other drugs acting through the oxytocin receptor could act as multifunctional analgesics with unique therapeutic value.

Effect of estrogen on bladder nociception in rats.

PURPOSE We assessed the effect of ovariectomy and estrogen replacement on nociceptive responses to bladder distention in a rat model. MATERIALS AND METHODS Female Sprague-Dawley rats (Harlan) underwent ovariectomy or sham surgery. Visceromotor responses (abdominal contractions) to bladder distention were determined 3 to 4 weeks later under isoflurane anesthesia. In rat subsets estrogen was chronically replaced with a subcutaneous estrogen pellet vs a placebo pellet or acutely replaced by subcutaneous injection 24 hours before testing. Effects of estrogen withdrawal were examined in another group of rats by implanting a pellet and explanting the pellet 24 hours before testing. Uterine weight was measured to assess the estrogen dose. RESULTS Visceromotor responses to bladder distention were significantly less vigorous in ovariectomized rats vs controls. Acute estrogen replacement increased visceromotor responses in these rats but chronic estrogen replacement did not. Sudden chronic estrogen withdrawal resulted in increased visceromotor responses. Uterine weight was consistent with the physiological estrogen dose. CONCLUSIONS Estrogen alone was not sufficient to produce increased nociceptive responses but an acute decrease in estrogen resulted in increased visceromotor responses. These data suggest that the pronociceptive effects of estrogen may be due to a mismatch between peripheral vs central and/or genomic vs nongenomic effects of the hormone, which occur during rapidly decreasing estrogen levels.

The amygdala central nucleus is required for acute stress-induced bladder hyperalgesia in a rat visceral pain model

Chronic stress has been implicated in the pathogenesis of chronic visceral pain conditions, such as interstitial cystitis (IC), and bouts of acute stress exacerbate clinical urological pain. Studies using animal models have shown that exposure to chronic footshock stress augments reflex responses to urinary bladder distension (UBD) in animal models, however acute effects in animal models are largely unknown, as are the central nervous system mechanisms of stress-related increases in nociception. The amygdala is a salient structure for integration of sensory and cognitive/emotional factors. The present study determined the role of the central nucleus of the amygdala (CeA) in stress-related bladder hypersensitivity. We examined the effects of CeA manipulations (lesions and chemical stimulation) on visceromotor responses (abdominal muscle contractions) to UBD in adult, female Sprague-Dawley rats. We report that acute footshock stress produces bladder hyperalgesia that can be prevented by bilateral CeA lesions, despite no effect of lesions on baseline somatic sensation, as indicated by flinch/jump thresholds to electrical shock. Further, acute glucocorticoid stimulation of the CeA recapitulated stress-induced hyperalgesia. Of note is that CeA lesions, but not chemical stimulation, significantly affected HPA axis activation, as indicated by measurements of circulating corticosterone. Our findings conclusively show that the CeA is necessary for the generation of bladder hyperalgesia in response to acute stress. The CeA may play multiple stress-related roles in nociceptive modulation, i.e., via direct facilitation of the HPA axis during acute stress, or via modulation of other systems that augment acute stress responsiveness.

Intrathecal oxytocin inhibits visceromotor reflex and spinal neuronal responses to noxious distention of the rat urinary bladder.

Background and Objectives Oxytocin (OXY) is a neuropeptide that has recently been recognized as an important component of descending analgesic systems. The present study sought to determine if OXY produces antinociception to noxious visceral stimulation. Methods Urethane-anesthetized female rats had intrathecal catheters placed acutely, and the effect of intrathecal OXY on visceromotor reflexes (VMRs; abdominal muscular contractions quantified using electromyograms) to urinary bladder distension (UBD; 10-60 mm Hg, 20 seconds; transurethral intravesical catheter) was determined. The effect of OXY applied to the surface of exposed spinal cord was determined in lumbosacral dorsal horn neurons excited by UBD using extracellular recordings. Results Oxytocin doses of 0.15 or 1.5 &mgr;g inhibited VMRs to UBD by 37% ± 8% and 68% ± 10%, respectively. Peak inhibition occurred within 30 minutes and was sustained for at least 60 minutes. The effect of OXY was both reversed and prevented by the intrathecal administration of an OXY-receptor antagonist. Application of 0.5 mM OXY to the dorsum of the spinal cord inhibited UBD-evoked action potentials by 76% ± 12%. Consistent with the VMR studies, peak inhibition occurred within 30 minutes and was sustained for greater than 60 minutes. Conclusions These results argue that intrathecal OXY produces an OXY receptor–specific antinociception to noxious UBD, with part of this effect due to inhibition of spinal dorsal horn neurons. To our knowledge, these studies provide the first evidence that intrathecal OXY may be an effective pharmacological treatment for visceral pain.