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.

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.

Contribution of myofascial trigger points to migraine symptoms.

UNLABELLED: This study evaluated the contribution of myofascial trigger points (TrPs) to migraine pain. Seventy-eight migraine patients with cervical active TrPs whose referred areas (RAs) coincided with migraine sites (frontal/temporal) underwent electrical pain threshold measurement in skin, subcutis, and muscle in TrPs and RAs at baseline and after 3, 10, 30, and 60 days; migraine pain assessment (number and intensity of attacks) for 60 days before and 60 days after study start. Fifty-four patients (group 1) underwent TrP anesthetic infiltration on the 3rd, 10th, 30th, and 60th day (after threshold measurement); 24 (group 2) received no treatment. Twenty normal subjects underwent threshold measurements in the same sites and time points as patients. At baseline, all patients showed lower than normal thresholds in TrPs and RAs in all tissues (P < .001). During treatment in group 1, all thresholds increased progressively in TrPs and RAs (P < .0001), with sensory normalization of skin/subcutis in RAs at the end of treatment; migraine pain decreased (P < .001). Threshold increase in RAs and migraine reduction correlated linearly (.0001 < P < .006). In group 2 and normal subjects, no changes occurred. Cervical TrPs with referred areas in migraine sites thus contribute substantially to migraine symptoms, the peripheral nociceptive input from TrPs probably enhancing the sensitization level of central sensory neurons. PERSPECTIVE: This article shows the beneficial effects of local therapy of active myofascial trigger points (TrPs) on migraine symptoms in patients in whom migraine sites coincide with the referred areas of the TrPs. These results suggest that migraine pain is often contributed to by myofascial inputs that enhance the level of central neuronal excitability.

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.

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

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

c-Fos expression in the spinal cord of female rats with artificial ureteric calculosis.

Rats with an artificial stone in the left ureter display spontaneous pain behavior (ureteral 'crises') and referred hyperalgesia/contraction in the ipsilateral oblique musculature. To evaluate neuronal activation in both sensitive and motor pathways in this model, c-Fos expression was studied in the spinal cord of calculosis rats vs. sham controls. Fos-labeled cells were never observed in sham controls. In stone rats, they were found in the T10-L2 segments, throughout the dorsal horn, significantly more on the left than the right side (P < 0.002). Fos-labeled cells were also found in lamina IX, containing motoneurons; at the T11-T12 level, these were significantly more on the left than the right side (P < 0.03). Nociceptive input from the ureter thus activates not only sensory but also efferent neurons in the spinal cord, suggesting the triggering of reflex arcs by the visceral focus.

Evaluation of indices of skeletal muscle contraction in areas of referred hyperalgesia from an artificial ureteric stone in rats.

This study examined indices of skeletal muscle contraction in a rat model of referred muscle hyperalgesia from artificial ureteric calculosis [left oblique muscle (OE) for ipsilateral stone]. In specimens from the left versus right OE of stone-implanted female rats, a significant increase was found in membrane fluidity (P<0.01) and Ca(2+)-ATPase activity (P<0.0001) and a significant decrease in 3H-ryanodine binding (P<0.0001) and in I band length/sarcomere length ratio (contraction index) (P<0.01). The increase in Ca(2+)-ATPase activity was directly and significantly related to the number of rats' ureteral 'crises' (P<0.02). The results indicate a state of contraction in the hyperalgesic muscle, whose extent correlates to the algogenic activity of the ureteral stone.

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. Four groups of 10 rats each (female, Sprague-Dawley) were treated twice a day, for 4 days, with i.p. injections of tramadol 1.25 mg/kg, 2.5 mg/kg, 5 mg/kg or saline, respectively. The first injection was delivered 45 min before laparotomy (under pentobarbital anaesthesia) for formation of the stone in the upper left ureter via injection of dental cement. All rats were video-taped 24 h non-stop from the immediate postoperative period until the 4th day for recording of behavioural ureteral crises indicative of colic pain. Lumbar muscle sensitivity was tested daily over the same period by verifying presence or absence of vocalization upon pinching of the parietal layers at L1 level, bilaterally, at a constant predefined pressure value with calibrated forceps. Tramadol significantly reduced number and global duration (ANOVA, P < 0.008 and P < 0.004) of ureteral crises with respect to saline and the effect was dose-dependent (linear regression analysis between doses and parameters of crises, P < 0.003 and P < 0.002). The drug also significantly reduced the incidence of referred muscle hyperalgesia (ANOVA, P < 0.0001). It is concluded that tramadol is highly effective in controlling pain phenomena from urinary stones and can represent a valid therapeutic approach in patients with urinary colics.

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

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.