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.

The contribution of reactive oxygen species to sarcopenia and muscle ageing.

Ageing is a complex process that in muscle in usually associated with a decrease in mass, strength, and velocity of contraction. One of the most striking effects of ageing on muscle is known as sarcopenia, a process that is the result of many cellular changes, such as a reduction in the number of motor units coupled with an increase in motor unit size, progressive denervation, decreased synthesis of myofibrillar components, atrophy due to disuse, accumulation of connective tissue, etc. It has been suggested that sarcopenia may be triggered by reactive oxygen species (ROS) that have accumulated throughout one's lifetime. ROS, which are generated by the addition of a single electron to the oxygen molecule, are formed in all tissues including muscle fibres and, especially, in the mitochondrial respiratory chain. Such reactive elements are usually quite harmful and result in oxidative stress that can damage other cellular components such as DNA, proteins, lipids, etc. resulting in further damage to the cells and tissues. As a consequence, the intra and intercellular membranes of the muscle fibers, in particular those of the Sarcoplasmic reticulum, may be modified and the Ca(2+) transport mechanism altered. During the ageing process ROS production may drastically increase because of an altered function of the respiratory chain and an insufficient functioning of the antioxidant cellular defences. How such an oxidative insult plays a role in the age-related decrease of muscle performance and mass has yet to be defined. What does have a clear role in the progression of sarcopenia is the significant reduction of the regenerative potential of muscle fibres. This reduction is due to a reduced pool of satellite cells that are usually recruited to replace damaged fibres and promote their regeneration. Exercise as a method to prevent or at least delay sarcopenia has been discussed in many scientific reports. While on the one hand, it seems clear that exercise is effective in reducing the loss of muscle mass, on the other it appears that physical activity increases both the mechanical damage and the accumulation of free radicals as a result of an increase in the aerobic metabolism of the muscles involved.

Efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter, randomized, crossover trial.

OBJECTIVE: To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. BACKGROUND: A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. METHODS: One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. RESULTS: Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P<.01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. CONCLUSIONS: This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.

Modification of the functional capacity of sarcoplasmic reticulum membranes in patients suffering from chronic fatigue syndrome.

In chronic fatigue syndrome, several reported alterations may be related to specific oxidative modifications in muscle. Since sarcoplasmic reticulum membranes are the basic structures involved in excitation-contraction coupling and the thiol groups of Ca(2+) channels of SR terminal cisternae are specific targets for reactive oxygen species, it is possible that excitation-contraction coupling is involved in this pathology. We investigated the possibility that abnormalities in this compartment are involved in the pathogenesis of chronic fatigue syndrome and consequently responsible for characteristic fatigue. The data presented here support this hypothesis and indicate that the sarcolemmal conduction system and some aspects of Ca(2+) transport are negatively influenced in chronic fatigue syndrome. In fact, both deregulation of pump activities (Na(+)/K(+) and Ca(2+)-ATPase) and alteration in the opening status of ryanodine channels may result from increased membrane fluidity involving sarcoplasmic reticulum membranes.

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.

Artificial ureteral calculosis in rats: behavioural characterization of visceral pain episodes and their relationship with referred lumbar muscle hyperalgesia.

In a rat model of artificial ureteral calculosis, the aim of the study was to characterize the behavioural manifestations of direct visceral pain and to evaluate the relationship between number, duration and complexity of the visceral episodes and the extent of referred lumbar muscular hyperalgesia. As evidenced by non-stop video-tape recordings over 4-14 days, almost 98% of stone-implanted rats showed episodes similar to the writhing behaviour characteristic of noxious visceral stimulation in animals. From one rat to another, these episodes varied from very few (1-3) to a very high number (+/- 60), lasted a few minutes to over 45 min and were of variable complexity, as evaluated via an arbitrary scale on the basis of the combination of movements. Their number and duration decreased significantly, in a linear fashion, as time passed after the operation, so that they were mostly concentrated during the first 3 days. Number, duration and complexity of episodes were reduced by chronic treatment with morphine in a dose-dependent fashion. Stone-implanted rats displaying visceral episodes also showed hyperalgesia of the ipsilateral oblique musculature, as evidenced by a decrease in the vocalization threshold to electrical muscle stimulation, which was maximum on the first 3-4 days after implantation but lasted up to 10 days. The visceral episodes and the muscle hyperalgesia showed a strict relationship of interdependence: a significant, direct linear correlation was found between number and duration of episodes and tendency to also develop a contralateral muscle hyperalgesia. By applying the results of the study to the interpretation of human pathology, referred lumbar muscle hyperalgesia from ureteral calculosis would appear to be a strict function of the colic pain experienced.

Effects of extracorporeal shock-wave lithotripsy on referred hyperalgesia from renal/ureteral calculosis.

In patients suffering from colics due to calculosis of one upper urinary tract the evolution in time of referred parietal hyperalgesia after stone fragment elimination promoted by extracorporeal shock wave lithotripsy (ESWL) was studied. Before ESWL, all patients presented clinical evidence (positivity to dermographism and Head's procedure, pinch palpation, digital pressure and Giordano's manoeuver) and instrumental signs (significant lowering of pain threshold to electrical tissue stimulation) of cutaneous, subcutaneous and muscular tissue hyperalgesia in the lumbar region of the affected side. After ESWL, hyperalgesia decreased in the three tissues, as shown by progressive change in the clinical tests and an increase in pain threshold to electrical stimulation in relation to the extent of stone fragment expulsion. In the stone-free condition, hyperalgesia had disappeared in the skin but remained to a mild and moderate extent in the subcutaneous tissue and muscle respectively. It is concluded that the persistence in time of referred hyperalgesia is only in part linked to the continuing presence and activity of the stone in the urinary tract. To a certain extent, the phenomenon seems to become independent of the primary focus, possibly as a result of plastic neuronal changes in the central nervous system which, triggered by afferent visceral inputs, are maintained even after their removal.

Comparison of the effects of ureteral calculosis and occlusion on muscular sensitivity to painful stimulation in rats.

An animal model of muscular hyperalgesia was developed. In humans, this disorder follows painful crises due to ureteral calculosis. Changes in vocalization thresholds to electrical stimulation of the obliquus externus muscle of both sides were studied in a group of rats with chronically implanted muscles before and after the production of a stone in one ureter. In another group of rats with implanted muscles, it had been verified preliminarily that these thresholds did not vary widely from day to day. On the contrary, a significant lowering in threshold (max 31%) in the muscle ipsilateral to the implanted ureter appeared the day after the production of the stone and persisted for the subsequent 10 days of observation, although less pronounced during the last 5 days. Hypersensitivity to manual pressure was also observed, mainly in the ipsilateral muscle, in most rats during the same period. In order to differentiate between the effects due to the presence of the stone in the ureteral lumen and those due to the spontaneous occlusion which frequently occurred in the implanted ureter, 2 other groups of rats were studied. In one, a unilateral ureteral ligature was performed; in the other, the production of a stone was combined with a ligature (placed distally to the stone). Ligature alone never induced any hyperalgesic effect. Stone plus ligature produced a marked hyperalgesia (max 39%) in the ipsilateral muscle, which lasted for only 5 days. It is concluded that the ureteral stone is the factor responsible for the appearance of muscular hyperalgesia.