Rosanna Lerza

Influence of endometriosis on pain behaviors and muscle hyperalgesia induced by a ureteral calculosis in female rats.

&NA; Endometriosis and urinary calculosis can co‐occur. Clinical studies have shown that both painful and non‐painful endometriosis in women are associated with enhanced pain and referred muscle hyperalgesia from urinary calculosis, but the mechanisms underlying this phenomenon are still poorly understood. The aim of this study was to develop an animal model adequate to explore this viscero‐visceral interaction in standardized conditions. Using a model of endometriosis previously developed to study reduced fertility and vaginal hyperalgesia, endometriosis (endo) or sham‐endometriosis (sham‐endo) was induced in rats by autotransplantation of small pieces of uterus (or, for sham‐endo, fat) on cascade mesenteric arteries, ovary, and abdominal wall. After the endometrial, but not the fat autografts had produced fluid‐filled cysts (3 weeks), urinary calculosis was induced by implanting an artificial stone into one ureter. Pain behaviors were monitored by continuous 24‐h videotape recordings before and after stone implantation. Referred muscle hyperalgesia was assessed by measuring vocalization thresholds to electrical stimulation of the oblique musculature (L1 dermatome). The data were compared with previously reported data from rats that had received only the stone. Neither endo nor sham‐endo alone induced pain behaviors. Following stone implantation, in endo rats compared to sham‐endo and stone‐only rats, pain behaviors specifically associated with urinary calculosis were significantly increased and new pain behaviors specifically associated with uterine pathology became evident. Muscle hyperalgesia was also significantly increased. To explore the relationship between the amount of endometriosis and that of ureteral pain behavior, two separate groups of endo rats were treated with either a standard non‐steroidal anti‐inflammatory drugs (ketoprofen) or placebo from the 12th to the 18th day after endometriosis induction. The stone was implanted on the 21st day. Ketoprofen treatment compared to placebo significantly reduced the size of the cysts and both ureteral and uterine pain behaviors post‐stone implantation. The size of the cysts showed a significant linear correlation with the post‐stone ureteral pain behaviors. In conclusion, endo increased pain crises and muscle hyperalgesia typically induced by a ureteral calculosis, and the ureteral calculosis revealed additional pain behaviors typically induced by uterine pathophysiology; and this enhancement was a function of the degree of endometriosis. This result closely reproduces the condition observed in humans and could be due to a phenomenon of ‘viscero‐visceral’ hyperalgesia, in which increased input from the cyst implantation sites to common spinal cord segments (T10‐L1) facilitates the central effect of input from the urinary tract.

A Randomized, Controlled Study Comparing a Lidocaine Patch, a Placebo Patch, and Anesthetic Injection for Treatment of Trigger Points in Patients With Myofascial Pain Syndrome: Evaluation of Pain and Somatic Pain Thresholds

BACKGROUND Myofascial pain syndrome (MPS), a regional pain condition caused by trigger points in muscle or muscle fascia, produces muscle pain, tenderness, and disability. The gold standard of treatment for MPS-infiltration of trigger points with anesthetic-may provoke discomfort to the patients and require medical intervention. OBJECTIVES This study was designed to compare the effects of a topical lidocaine patch, a placebo patch, and injection of anesthetic (infiltration) for the symptoms of MPS in terms of pain, disability, and local tissue hypersensitivity, and to determine the acceptability of the lidocaine patch to the patients. METHODS Patients were randomly allocated to receive 1 of 3 treatments: a lidocaine patch applied to the trigger point for 4 days (replacement every 12 hours; total daily dose, 350 mg), a placebo patch applied to the trigger point for 4 days (replacement every 12 hours), or infiltration of the trigger point with two 1-mL injections of 0.5% bupivacaine hydrochloride given 2 days apart. Treatment with the patches was double-blinded, whereas treatment with infiltration was single-blinded. The number of pain attacks, pain intensity at rest and on movement, and pain-related interference with daily activity, work activity, mood, and quality of life were recorded before, during, and after treatment using a visual analog scale (VAS). Pressure and electrical pain thresholds of the skin, subcutis, and muscle in the trigger point, target area, and a pain-free area were evaluated before starting therapy (day 1) and on days 5 and 9. A VAS was used to measure discomfort from therapy, and a diary was given to each patient to record requests for additional treatment (if needed) and adverse effects. RESULTS Sixty white patients (46 women and 14 men) 19 to 76 years of age were studied. Mean (SD) age was 46.88 (15.37) years, and mean (SD) weight was 69.58 (13.94) kg. Twenty patients were assigned to each treatment group. Subjective symptoms did not change with placebo, but decreased significantly with the lidocaine patch and infiltration (both, P < 0.001) relative to baseline. Pain thresholds did not vary with the placebo patch, but increased significantly with the lidocaine patch and infiltration (all, P < 0.001); effects at muscle trigger points and target areas were greater with infiltration. Discomfort from therapy was greater with infiltration than with the lidocaine patch. Only patients in the placebo group requested additional treatment (P < 0.001). No adverse events occurred in any group. CONCLUSION Lidocaine patches were effective in, and highly acceptable to, these patients with MPS and high tissue hypersensitivity.

Modulation of pain and hyperalgesia from the urinary tract by algogenic conditions of the reproductive organs in women.

This study investigated the impact of algogenic conditions of the reproductive organs upon urinary pain perception in women. A 5-year survey was conducted among 69 fertile women with calculosis of one upper urinary tract via an ad-hoc questionnaire. At both retrospective (3 years) and prospective (2 years) investigation, dysmenorrheic women (D) reported more colics than non-dysmenorrheic women (ND) (P<0.001) and women with previous dysmenorrhea treated with estroprogestins (DH)(P<0.05). Pain thresholds (electrical stimulation) of the oblique musculature ipsilateral to the stone (L1, site of referred hyperalgesia from upper urinary tract) were lower in D than in ND (P<0.01) and DH (P<0.05). Calculosis women with asymptomatic endometriosis / ovarian cysts also reported more colics (6-month prospective study) and greater threshold lowering (P<0.05) than women with calculosis alone. The results show enhancement of urinary pain / hyperalgesia by both manifest and latent algogenic conditions of the female reproductive organs. This enhancement could derive from neuronal sensitization in spinal segments of common projection of the two visceral districts (T10-L1).

Relationship between pain symptoms and referred sensory and trophic changes in patients with gallbladder pathology

&NA; The relationship was investigated between algogenic potential of gallbladder pathology and occurrence/extent of sensory and trophic changes in the referred area. Five groups of subjects were studied, with: symptomatic gallbladder calculosis (3–20 colics); asymptomatic calculosis; symptomatic gallbladder shape abnormality (8–18 colics); asymptomatic shape abnormality; normal gallbladder/no symptoms. At the cystic point (CP) and contralaterally, all underwent measurement of: pain thresholds to electrical stimulation of skin, subcutis and muscle; thickness of subcutis and muscle via ultrasounds. Contralaterally to CP, all thresholds were not significantly different in the five groups. At CP, subcutis and muscle thresholds were significantly lower in symptomatic vs asymptomatic patients and/or normals (0.0001<P< 0.05). In symptomatic cases, at CP compared to contralaterally, subcutis and muscle thresholds were significantly lower (0.0001<P<0.02), subcutis thickness was significantly higher and muscle thickness significantly lower (0.006<P<0.02). Subcutis and muscle thresholds at CP in symptomatic patients were significantly and inversely correlated linearly to the number of colics (P<0.0004; P<0.0001). Patients with symptomatic calculosis were re‐evaluated after 6 months; those not presenting further colics showed a significant increase in subcutis and muscle thresholds at CP, while those who continued presenting colics showed a further significant threshold decrease (0.01<P<0.05); tissue thickness did not vary. Referred hyperalgesia and altered trophism from the gallbladder only occur in painful pathology, their extent being modulated by the amount of perceived pain. The results suggest different mechanisms by which visceral nociceptive inputs trigger sensory vs trophic changes in the referred area.

Sensitivity disturbances in patients with irritable bowel syndrome and fibromyalgia.

BACKGROUND:Although visceral hypersensitivity is a common feature among patients with irritable bowel syndrome (IBS), studies on somatic sensitivity have given controversial results.AIM:To assess visceral sensitivity in response to isotonic rectal distensions and somatic sensitivity at different layers of the body wall (skin, subcutis, and muscle) in patients with IBS and fibromyalgia (FM), within and outside the area of abdominal pain referral.MATERIALS AND METHODS:We studied 10 patients with IBS, 5 patients with FM, 9 patients with IBS+FM, and 9 healthy controls. Rectal distensions were performed by increasing tension at 4 g steps up to 64 g or discomfort. Pain thresholds to electrical stimulation were measured within and outside the areas of abdominal pain referral.RESULTS:Patients with IBS and IBS+FM demonstrated rectal hypersensitivity in comparison to controls. The threshold of discomfort was 44 ± 5 g in IBS and 36 ± 5 in IBS+FM patients, while patients with FM and healthy controls tolerated all distensions without discomfort. In the areas of pain referral, pain thresholds of all three tissues of the body wall were lower than normal in all patients groups (p < 0.001). In control areas, the pain thresholds were normal in skin, and lower than normal in subcutis and muscle in IBS (p < 0.001). FM and IBS+FM demonstrated somatic hypersensitivity at all sites (p < 0.001 vs healthy).CONCLUSION:Our observations seem to indicate that, although sharing a common hypersensitivity background, multiple mechanisms may modulate perceptual somatic and visceral responses in patients with IBS and FM.

Estradiol and testosterone differently affect visceral pain-related behavioural responses in male and female rats

In the study of pain, the presence of sex differences is well known, with female subjects being more affected in a number of chronic painful conditions; however, the underlying mechanisms and the involvement of gonadal hormones, are still controversial. This study evaluated visceral pain in a validated rat model of artificial calculosis and the effects of estradiol and testosterone administration. Adult male and female rats were divided into groups and treated with one of the substances or Oil (vehicle) for 5 days, starting 2 days before surgery, with half receiving an artificial calculosis (Stone) and half only a sham (Sham) procedure. The animals’ behaviour (ureteral crises, frequency and duration) were recorded for 72 h; estradiol and testosterone plasma levels were determined in all groups at the end of the observation period. After surgery, only Stone rats showed ureteral pain crises, with a significant sex difference in the Oil‐treated groups in which the number and duration of crises were higher in females than in males. This difference was not present in the estradiol‐treated groups in which ureteral crises were decreased only in females while testosterone treatment had no effect in either sex. Estradiol and testosterone plasma levels were affected by treatments in both sexes. These results confirm that, also in this model of visceral pain, females experience more pain than males; moreover, they show that supraphysiological levels of estradiol, but not of testosterone, are analgesic only in females. A dose and sex‐dependent efficacy of gonadal hormones is suggested and discussed.

Effects of tramadol on behavioural indicators of colic pain in a rat model of ureteral calculosis

This study investigated the effect of prolonged administration of tramadol vs. placebo on behavioural indicators of ureteral pain and referred lumbar muscle hyperalgesia in a rat model of artificial ureteral calculosis.

Neurophysiological Basis of Visceral Pain

SUMMARY Objectives: In spite of visceral pain being a prominent symptom in the clinical setting, its mechanisms have been less explored than those underlying somatic pain. The objectives of this article are to review the current knowledge on pathophysiology of the most prominent phenomena related to visceral nociception, i.e., true visceral pain, referred pain without and with hyperalgesia, visceral hyperalgesia, and viscero-visceral hyperalgesia. Findings: The poor localization and diffuse nature of true visceral pain results from the low density of sensory innervation of the viscera and the extensive functional divergence of the visceral input within the central nervous system [CNS]. Referred pain without hyperalgesia is explained by the phenomenon of “convergence-projection,” i.e., convergence of visceral and somatic afferent fibers onto the same sensory neurons at various CNS levels. Referred pain with hyperalgesia is partly due to central sensitization of viscero-somatic convergent neurons [triggered by the massive afferent visceral barrage]. The muscle hyperalgesia also probably results from a reflex arc activation; the visceral input would trigger reflex muscle contraction in turn responsible for sensitization of muscle nociceptors in the area of referral. Recent experimental studies by this group in a rat model of ureteric calculosis support this hypothesis by documenting: a. positivity of a number of morphofunctional indices of skeletal muscle contraction in specimens of the oblique musculature ipsilateral to the stone [site of referred hyperalgesia] and b. c-Fos labeled motoneurons in the spinal cord segments of sensory projection from the ureter. Visceral hyperalgesia, e.g., hypersensitivity of an internal organ due to inflammation, has been attributed to phenomena of both peripheral and central sensitization. Viscero-visceral hyperalgesia, i.e., the enhancement of painful symptoms because of algogenic conditions of two visceral districts sharing part of their sensory innervation [e.g., urinary tract and female reproductive organs] is probably explained, at least in part, by sensitization of viscero-visceral convergent neurons in the CNS. Conclusions: Some aspects of visceral nociception have been fully elucidated, while the pathophysiology of other phenomena–mostly referred hyperalgesia from viscera and viscero-visceral hyperalgesia–still needs clarification. Experimental studies on adequate animal models will hopefully provide a better understanding of these phenomena, leading ultimately to an improvement of diagnostic tools and management of visceral pain in the clinical setting.

373 VISCERAL PAIN, REFERRED MUSCLE HYPERALGESIA AND THE AGING PROCESS: EXPERIMENTAL STUDY IN A RAT MODEL OF ARTIFICIAL URETHRAL CALCULOSIS

animals. Spatial firing and place field characteristics of the cells were examined before (10 days) and after (21 days) peripheral nerve injury (SNI). The findings showed an increase of the number of place fields encoded per cell and an increase of the place field size (expansion) after nerve injury. In addition, the infield coherence increases for the SNI-group and amount of spatial information (specificity) content that a single spike conveyed about the animal location decrease over time. However, other measures of spatial tuning (e.g. infield firing rate, firing peak and number of spikes) were unchanged between the two experimental groups. The current study suggests that there is a relative instability of hippocampal place cells across the installation of the peripheral pain condition in a well-trained task. Supported by FCT Grant-SFRH/BD/42500/2007 and BIAL Project126/08.

180 SEX DIFFERENCES IN BEHAVIORAL RESPONSES TO ARTIFICIAL CALCULOSIS IN RATS

A-K. Persson1 °, Z. Wiesenfeld-Hallin2, M. Devor3, X-J. Xu2, K. Fried1. 1Department of Odontology, Center for Oral Biology, Karolinska Institutet, Huddinge 2Department of Clinical Neuroscience, Section of Clinical Neurophysiology, Karolinska University Hospital Huddinge, Huddinge, Sweden, 3Department of Cell & Animal Biology, Institute of Life Sciences and Center for Research on Pain, Hebrew University of Jerusalem, Jerusalem, Israel