Referred Pain Area Research Articles

Sex differences in temporal characteristics of descending inhibitory control: an evaluation using repeated bilateral experimental induction of muscle pain

Little is known about sex differences in the temporal pattern of descending inhibitory mechanisms, such as descending noxious inhibitory control (DNIC). Sex differences in temporal characteristics of DNIC were investigated by measuring pressure pain thresholds (PPTs) over time in the trapezius muscles (local pain areas) and the posterolateral neck muscles (referred pain areas) following repeated bilateral injection of hypertonic versus isotonic saline into both trapezius muscles. Ten females and 11 males received two consecutive bilateral injections, with 15 min interval, of either 5.8% hypertonic saline (0.5 ml in each side for each bilateral injection) or isotonic saline as a control in a randomized manner. Following hypertonic saline injection, the maximal pain intensities of the first and second bilateral injections were significantly higher in females than in males. The PPTs in the trapezius muscles were significantly lower in females than in males. Significantly higher PPTs (hypoalgesia) in men than in women were shown 15 min after the first bilateral injection, and 7.5 and 15 min after the second bilateral injection in the referred pain areas. Importantly, the second bilateral injection failed to further increase the PPTs for both sexes. These results showed that there were sex differences in temporal characteristics of descending inhibition with long-lasting hypoalgesia in men than in women. Repeated noxious muscular stimuli may inhibit further build-up of DNIC, which may reflect a mechanism of plasticity of the descending inhibitory systems following recurrent nociceptive barrage for both sexes.

MULTIDISCIPLINARY PAIN ABSTRACTS: 17 . Clinical Science (17)

The aim of this study was to investigate the effect of multimodal visceral pain stimuli of the esophagus in healthy subjects before and after induction of visceral hyperalgesia. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia. The multimodal psychophysical responses and reflex sizes were assessed twice before sensitization, and the parameters were reproducible. The authors concluded that visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multimodal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short‐lasting visceral hyperalgesia can generate generalized sensitization.

Dipolar source modelling of brain potentials evoked by painful electrical stimulation of the human sigmoid colon

The aim of the study was to compare the cerebral generators following painful stimulation of the sigmoid colon and the abdominal skin in 11 healthy subjects. The evoked potentials (EPs) were recorded from 31 surface electrodes following painful electrical stimuli of the sigmoid colon, and of the referred pain area on the abdomen. Current dipole models estimating the EPs amplitude and topography were calculated. For colon stimulation, the earliest cortical activities were described by dipoles in the bilateral insula and in the anterior cingulate cortex, while both secondary somatosensory areas were activated later. When the skin was stimulated, early bilateral dipoles in the primary and secondary somatosensory areas were estimated, followed by a dipole in the frontal region. This suggests that painful cutaneous and visceral stimuli are processed differently in the brain.

Somatosensory changes in the referred pain area in patients with acute cholecystitis before and after treatment with laparoscopic or open cholecystectomy

Background: Visceral pain can lead to hypersensitivity in the referred pain area. In patients with chronic visceral pain this somatic hypersensitivity can persist for years. As 25%–40% of patients continue to have symptoms after cholecystectomy, whereof no explanation for pain can be offered in up to 30%, it could be hypothesized that altered sensory characteristics induced by acute cholecystitis could persist in some patients and thus be responsible for postcholecystectomy pain. The aim of this study was to investigate the somatosensory sensitivity in the referred pain area in patients with acute cholecystitis before and after cholecystectomy. Methods: Patients with acute cholecystitis were studied before (n = 30) and after (n = 18) treatment. Sensitivity to pinprick, heat, cold, pressure and single and repeated electrical stimulation was studied in the referred pain area and in the control area on the contralateral side of the abdomen. Results: Significant hypersensitivity in the referred pain area was detected in patients with acute cholecystitis. The somatic sensitivity was normalized after cholecystectomy. Conclusions: Acute cholecystitis leads to hypersensitivity in the referred pain area. Persistent hypersensitivity, as earlier reported after chronic visceral pain, was not seen aftiser cholecystectomy, indicating that this mechanism may not play a major role in patients with postcholecystectomy pain syndrome. The possible role in patients operated on for chronic gallstone pain has still to be investigated.

Central sensitisation and cutaneous allodynia in migraine: implications for treatment.

Cutaneous allodynia, pain resulting from application of a non-noxious stimulus to normal skin, is a recently described symptom of migraine, with a potential role in directing optimal treatment for migraine attacks. Manifestations of cutaneous allodynia include discomfort when combing the hair, shaving, and wearing glasses, contact lenses, earrings or tight clothing. The exact mechanism by which a migraine attack is triggered is not known, but it has been theorised that, in some patients, once the attack has begun, central neurons can propagate information about the pain process without the need for further external stimuli. This process is termed central sensitisation. The trigeminal nerves, which innervate intracranial and extracranial tissues, account for head pain and other symptoms in migraine. The first-order neurons in the trigeminal ganglion receive input from the dural blood vessels, which is transmitted to second-order neurons in the trigeminal brain stem nuclear complex and is finally sent to the third-order neurons in the thalamus. Studies in humans and animals have shown that migraine pain progresses along this neural pathway, with throbbing head pain occurring early in the attack (sensitisation of first-order neurons), followed by central sensitisation and cutaneous allodynia within the referred pain area (second-order) and finally extracephalic allodynia (third-order). The data also indicate that once central sensitisation is established in the second- and third-order neurons, migraine treatment designed to prevent the initiation of central sensitisation can lessen the pain to some extent but cannot reverse it. Thus, treatment affecting the initiation of central sensitisation should be administered immediately after the onset of migraine pain to prevent intracranial hypersensitivity and the establishment of allodynia. The serotonin 5-HT(1B/1D) agonist anti-migraine agents (the 'triptans') block meningeal nociceptor transmission at presynaptic sites in the dorsal horn. Studies have shown that triptan therapy can abort pain prior to the development of central sensitisation, but not after allodynia has been established. Therefore, in the subset of patients who report symptoms of cutaneous allodynia with migraine attacks, early initiation of triptan therapy is currently the best intervention to achieve rapid, complete and sustained pain relief.

Hypoalgesia to pressure pain in referred pain areas triggered by spatial summation of experimental muscle pain from unilateral or bilateral trapezius muscles

Animal and human experimental studies have suggested the importance of spatial summation in the nociception processing and in the activation of descending inhibition. However, the relationship between the areas (size) of muscles stimulated and the recruitment of descending inhibition has not been addressed. Consequently, we tested whether bilateral versus unilateral injection of hypertonic saline into trapezius muscles caused hypoalgesia to pressure pain (pressure pain thresholds, PPTs) in the local pain areas (the trapezius muscles) and the referred pain areas (the posterolateral neck muscles). Two groups of volunteers participated. One group received a unilateral injection (one injection) and the other group bilateral injections (two injections). In the bilateral group, hypertonic saline was injected in one trapezius first, and 45 s later, while pain was still present from the first injection, a second injection was performed into the contralateral trapezius muscle. The saline-evoked time to maximal pain was significantly shorter after the second injection than after the first injection. More subjects developed referred pain after the bilateral compared with the unilateral injection. In the referred pain areas, the PPTs 7.5 and 15 min after the second injection were significantly increased compared with the first injection, while no changes in the PPT were observed in local and referred pain areas after unilateral injection. This suggests that the induction of descending inhibition was triggered by spatial summation during the later phase of experimentally induced muscle pain. The present experimental model might be used for further investigation of descending inhibition related to the spatial characteristics of nociceptive stimuli in humans.

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

Background and aims. Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi-modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi-modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia. Methods. A probe for multi-modal (cold, warm, electrical, and mechanical) visceral stimulation was positioned in the lower part of the oesophagus in eleven healthy subjects. Mechanical stimuli were applied as distensions with a bag, which also had electrodes mounted for electrical stimulation. Thermal stimulation with temperatures from 0 to 60 °C was applied with re-circulating water in the bag. To assess the interaction between visceral and somatic pathways, the nociceptive withdrawal reflex to electrical stimuli at the ankle was measured with and without simultaneous mechanical oesophageal distension to painful levels. Finally, the oesophageal sensitisation was induced by perfusion with hydrochloric acid. Multimodal responses (pain threshold, stimulus response function, size of nociceptive reflex, and referred pain areas) were assessed before and after the induced hyperalgesia. Results. The multi-modal psychophysical responses and reflex sizes were assessed twice before sensitisation, and the parameters were reproducible. Sensitisation of the oesophagus resulted in hyperalgesia to electrical and mechanical stimuli (29 and 35% decrease in pain threshold) and allodynia to cold and warmth stimuli (11% increase in sensory rating). After sensitisation, the referred pain area to mechanical stimuli increased more than 300% with a change in the localisation of the referred pain to all stimuli, and the amplitude of nociceptive reflex increased 100%, all indicating the presence of central hyperexcitability. Conclusions. Visceral hyperalgesia/allodynia can be induced experimentally and assessed quantitatively by the newly introduced multi-modal psychophysical assessment approach. The significant changes of the experimentally evoked referred pain patterns and of the nociceptive reflex evoked from a distant somatic structure indicate that even short-lasting visceral hyperalgesia can generate generalised sensitisation.

Central sensitization in fibromyalgia and other musculoskeletal disorders.

Muscle hyperalgesia and referred pain play an important role in chronic musculoskeletal pain. New knowledge on the involved basic mechanisms and better methods to assess muscle pain in the clinic are needed to revise and optimize treatment regimens. Increased muscle sensitivity is manifested as pain evoked by a normally non-nociceptive stimulus (allodynia), increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or increased referred pain areas with associated somatosensory changes. Some manifestations of sensitization, such as expanded referred muscle pain areas in patients with chronic musculoskeletal pain, can be explained from animal experiments showing extrasegmental spread of sensitization. An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may result from peripheral and central sensitization, which may play a role in the transition from acute to chronic pain.

Endometriosis is associated with central sensitization: a psychophysical controlled study

Endometriosis is a pain syndrome representing a major cause of pelvic pain in women of reproductive age. The aim of this study was to test the hypothesis that persistent nociceptive input from endometriotic tissues leads to central sensitization manifested by somatic hyperalgesia and increased referred pain areas to experimental saline-induced muscle pain in patients with endometriosis, compared to healthy control subjects. Ten women with laparoscopically confirmed endometriosis and 10 healthy, age-matched women participated in the study. Hypertonic saline (0.5 mL, 5.8%) was injected intramuscularly, in random succession, into 1 site of menstrual pain referral (the multifidus muscle at the low back) and into 1 non-pain control site (first dorsal interosseous muscle [FDI] of the hand). The post-saline pain intensity and pain areas at the FDI were significantly greater in patients with endometriosis than in control subjects ( P < .05) but were not different between the groups for the back. An absence of enhancement of post-saline pain responses at the back in the endometriosis group suggests that saline-induced pain at the back appears to activate segmental inhibitory systems in patients with endometriosis. Manifestation of central sensitization in women with endometriosis is demonstrated by increased muscle nociceptor input in the form of increased post-saline pain intensity, pain areas at the FDI, and hypersensitivity to pressure stimulation. These findings provide new insights into the complex pain mechanisms associated with endometriosis.

Perceptual integration of intramuscular electrical stimulation in the focal and the referred pain area in healthy humans

The aim of the study was to investigate the perceptual integration of simultaneous stimulation in a focal and a referred pain area to investigate whether referred pain is mainly caused by facilitation of on-going input from the referred pain area by stimulation in the focal pain area or if referred pain is a consequence of misinterpretation of the origin of inputs from the focal pain area. Pain was induced in twelve healthy individuals by intramuscular electrical stimulation in the left infraspinatus muscle (MI) or the left dorsolateral upper arm (UA), i.e. the area of referral commonly reported from stimulation in MI. Conditioning stimulation consisted of, in a counterbalanced order, no stimulation (baseline) and pain intensity rated as 2/10 and 4/10, respectively, on a category scale. During conditioning stimulation in MI, sensitivity to test stimuli was assessed in UA and vice versa. The test stimuli consisted of i.m. electrical stimulation corresponding to the perception threshold to innocuous electrical stimulation, the electrical pain threshold (EPT), and pain intensity rated as 2/10, 4/10 and 6/10, respectively. Conditioning stimulation corresponding to 2/10 did not result in a statistically significant change in sensitivity to any test stimuli in either location. During conditioning stimulation corresponding to 4/10 in m. infraspinatus, all twelve subjects reported referred pain in the dorsolateral upper arm. Compared to baseline, EPTs decreased in the referred pain area ( P<0.001), while no other statistically significant changes in sensitivity to test stimuli were seen. Conditioning stimulation corresponding to 4/10 in the dorsolateral upper arm gave rise to referred pain in one individual (area of m. biceps brachii), and no statistically significant changes were seen in the sensitivity to electrical stimuli in m. infraspinatus. In conclusion, an effect at pain threshold level only was documented during simultaneous stimulation in the focal and referred pain area, which does not support facilitation of inputs from the referred pain area as the main mechanism generating referred pain. Instead, referred pain is most likely a consequence of misinterpretation of the origin of input from the stimulated focal pain area, due to excitation of neurones somewhere along the neuroaxis with projected fields in the referred pain area. The fact that conditioning stimulation in m. infraspinatus generated referred pain in the dorsolateral upper arm, but not vice versa suggests that the divergence of the input is not reciprocally arranged.

Gut pain and hyperalgesia induced by capsaicin: a human experimental model

Human experimental visceral pain models using chemical stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chemical activators (capsaicin, glycerol) and measure quantitatively the induced hyperexcitability to painful mechanical gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing volumes of capsaicin 50 μg/ml (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 ml), glycerol (2.5, 5, and 10 ml) or saline (2.5, 5, and 10 ml) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions separated by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. ‘Boring’ and ‘hot’ pain were evoked in all subjects by low doses (median 0.5 ml) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, respectively. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% reduction pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mechanical hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clinical relevant visceral pain mechanisms.

Pain and biomechanical responses to distention of the duodenum in patients with systemic sclerosis

Background & Aims: Abnormalities of the small intestine have been indicated in systemic sclerosis. The aim was to use a new method to study the active-passive mechanical and sensory properties of the duodenum in these patients. Methods: A volume-controlled ramp-distention protocol was used in the duodenum in 9 patients and 8 healthy controls. The nonpainful/painful sensations, pressure, cross-sectional area, wall tension, and strain were evaluated. Using butylscopolamine for muscle relaxation, the active (contractile muscular component) and passive (other mechanical tissue components) were computed. Results: The contraction amplitude was smaller and the cross-sectional area higher in the patients ( P < 0.05). Both the active and passive tension as function of strain was translated to the left in the patients, indicating a stiffer wall. The maximum active tension and the corresponding strain were 62% and 69% lower in the patients ( P < 0.05). An association was found between the duration of the disease and the strain ( P < 0.05). The perception score was higher as function of pressure, tension, and strain ( P = 0.01, P = 0.03, and P < 0.01, respectively) in the patients than in the controls, with strain as the most sensitive variable to describe the sensory response. In 5 patients who complained of regular clinical symptoms, the referred pain area to distention was enlarged. Conclusions: Systemic sclerosis resulted in increased stiffness and impaired muscle function of the duodenum. The pain evoked by a controlled strain of the gut was increased and can explain many of the symptoms reported in the clinic.

Short latency cerebral response evoked by painful electrical stimulation applied to the human sigmoid colon and to the convergent referred somatic pain area.

Background. The brain-gut interaction is important for the understanding of pain mechanisms related to gastroenterological diseases. Unfortunately little is known about the early cerebral events related to the processing of gut-evoked pain. The aims of this human study were (1) to investigate the early-evoked brain potentials (EPs) to painful sigmoid colon stimulation and (2) to evaluate the EPs evoked from the convergent referred skin pain area after this area was induced by the painful gut stimulation. The background for the second aim was to evaluate whether the convergent input between somatic and visceral structures could induce detectable short-term cortical reorganization. Methods. Eleven subjects (nine men) participated; the mean age was 39.5+/-11.9 years. The gut-evoked EPs (recorded from 31 scalp sites) were evoked by electrical stimulation 30 cm from the anal verge by a modified biopsy forceps, inserted through a sigmoidoscope. The painful gut stimulation elicited a characteristic pain pattern referred to the abdomen. The short latency somatosensory evoked potentials were evoked from the skin inside and outside the referred pain area elicited by gut stimulation. A total of 750 electrical stimuli were delivered to the gut at slight painful stimulus intensity and 500 stimuli were delivered to the skin. Results. Short-latency EPs to electrical gut stimulation with an onset of 50-60 ms could be recorded. The gut EP topography revealed three consecutive positive peaks (P63, P101, P145) towards the frontal area. Centroparietal negativities (N128 and N222) were found, which were followed by two central positivities (P269 and P352). The somatic and gut evoked EPs differed in morphology and topography, but the EPs to skin stimulation inside and outside the gut-evoked referred pain area did not differ significantly. Conclusion. Short latency (50-60 ms) EPs to painful electrical sigmoid colon stimulation were demonstrated, reflecting an early cortical processing of sensory input from the sigmoid colon. The early cortical processing of somatic input from experimentally evoked visceral referred pain areas did not cause any detectable short-term cortical reorganization.

Experimental muscle pain provokes long-lasting alterations of thermal sensitivity in the referred pain area

This study explores thermal sensitivity and thermal nociception for signs of central sensitization in the area of referred muscle pain. Two groups of 24 healthy subjects (ss) each, and with mean ages of, respectively, 27 and 55 years, were first trained in quantitative sensory testing and pain rating. Then, in a second session, referred pain was evoked by injection of 6% hypertonic saline into the infraspinatus muscle. Cold and warm thresholds, synthetic heat threshold (SHT – evoked by an alternating pattern of adjacent cold and warmth), and thermal pain thresholds were measured within the referred pain area at a rate of 1/20 min for 60–120 min. All ss of both groups experienced referred pain mostly in the upper arm and of medium intensity. Pain lasted for approximately 12 min with a shorter duration in the older group ( p<0.02). The cold threshold increased significantly ( p<0.001), and the warm threshold slightly, after the injection and remained high for the whole observation period (i.e. lower and higher temperatures were necessary to elicit cold and warmth, respectively). Threshold recovery was more delayed in the older age group. Of those 28 ss in whom cold pain threshold could be followed during the whole observation period, 18 ss showed an immediate threshold decrease of average 6 °C which outlasted the observation period. Four ss responded with a threshold increase. Heat pain thresholds were not affected in the referred pain area. Average synthetic heat threshold did not change; there were, however, distinct and lasting individual threshold shifts in either direction. Ss with lowered cold pain thresholds or evident threshold shifts for synthetic heat had also higher pain ratings. The results demonstrate that experimental muscle pain can induce long-lasting changes in thermal sensitivity and nociception. The unexpected cold threshold increase may tentatively be explained as an expression of long-term depression. The decrease of cold pain threshold or SHT in subgroups of ss may indicate central sensitization. However, the observed changes in this experiment do not provide an unambiguous indicator for central sensitization which seems to be rather individual and might depend on pain intensity and proneness to express central mechanisms of sensitization. Therefore in clinical pain states the individual pattern of sensory abnormalities has to be analysed and interpreted in addition to the pain parameters to assess central involvement.

The influence of experimental pain intensity in the local and referred pain area on somatosensory perception in the area of referred pain

The aim of this study was to investigate the influence of experimental pain intensity in the local and referred pain area on somatosensory perception thresholds in the area of referred pain. Pain was induced by intramuscular electrical stimulation of the left infraspinatus muscle in 12 healthy individuals. The stimulation corresponded to the local pain threshold (‘mild local pain’), the referred pain threshold (‘mild referred pain’), and a pain intensity corresponding to 2 on a 10-point category scale in the referred pain area (‘moderate referred pain’). Quantitative sensory testing was performed to assess perception thresholds in the referred pain area and the homologous contralateral area before and during stimulation. Perception thresholds to light touch (LTTs), pressure pain (PPTs), and to innocuous as well as noxious warmth and cold were assessed. During stimulation the LTTs increased in the referred pain area compared to baseline, uninfluenced by pain intensity. Perception thresholds to innocuous cold and warmth increased bilaterally during the stimulation, without relation to pain intensity. Heat pain thresholds were not affected. Compared to baseline, PPTs increased bilaterally during stimulation corresponding to ‘mild local pain’ and ‘mild referred pain’, respectively, and a further increase was seen during ‘moderate referred pain’. The decreased sensitivity to innocuous cold, warmth, and pressure pain was bilateral, indicating activation of endogenous net inhibitory mechanisms interacting bilaterally. We found no influence of pain intensity on somatosensory thresholds restricted to the referred pain area and light touch was the only affected modality in the referred pain area only.

Deep Tissue Hyperalgesia

SUMMARYObjectives: The aim of this paper is to give a brief introduction to the mechanisms and manifestations related to muscle hyperalgesia. It has become increasingly evident that muscle hyperalgesia plays an important role in chronic musculoskeletal pain. Better understanding of the involved basic mechanisms and better methods to assess muscle pain in the clinic might provide new possibilities for designing rational therapies and for targeting the pharmacological intervention optimally.Results: Increased muscle sensitivity can be manifested as either 1. pain evoked by a normally nonnociceptive stimulus [allodynia], 2. increased pain intensity evoked by nociceptive stimuli [hyperalgesia], or 3. increased referred pain areas with associated somatosensory changes. For basic experimental studies quantitative sensory testing provides the possibility to evaluate these manifestations in a standardized way in patients suffering from musculoskeletal pain or in healthy volunteers.Conclusions: Increased muscle se...

Cerebral Response to Electric Stimulation of the Colon and Abdominal Skin in Healthy Subjects and Patients with Irritable Bowel Syndrome

Background: Visceral hyperalgesia may play an important part in the pathophysiology of the irritable bowel syndrome (IBS). We investigated the neuronal afferent pathways in healthy volunteers and IBS patients by recording evoked potentials (EPs) elicited by electrical stimulation of the colon and abdominal skin inside and outside the referred pain area. Methods: Six healthy subjects and nine IBS patients met the inclusion criteria. Morphology and topography of EPs to painful electrical stimuli were estimated in the rectosigmoid junction and on the skin inside/outside the referred pain areas. Results: The EPs to painful stimuli of the gut showed a shorter latency and a smaller amplitude of the first positive peak (P1) in the IBS group. The controls had a mid-latency frontal positive component after 100 ms, whereas no reliable early activation was seen in the IBS patients. In controls, a single late (> 150 ms) positive component was seen, whereas the late component was biphasic in the IBS group. The EPs to painful stimuli of the two skin areas differed in IBS patients, but not in controls. Conclusion: Differences in the EPs to electrical painful stimulation of the sigmoid colon and skin inside/outside the experimentally evoked referred pain area were seen comparing healthy subjects and IBS patients. The results indicate altered central nervous system responses.

SIMILARITY OF DISTRIBUTIONS OF SPINAL C-FOS AND PLASMA EXTRAVASATION AFTER ACUTE CHEMICAL IRRITATION OF THE BLADDER AND THE PROSTATE

Persistent pain in referred areas and voiding dysfunction are characteristic symptoms of chronic abacterial prostatitis. Since referred pain from visceral organs is considered a neurological event, it appeared reasonable to hypothesize that the persistent pain associated with prostatitis might also be explained by neural mechanisms. Neurogenic plasma extravasation and c-fos expression in the spinal cord, after chemical irritation of the rat prostate, was identified as a method to investigate the neurogenic aspect of prostatic inflammation. The distribution of plasma extravasation using Evans blue dye was determined after chemical irritation of the prostate and bladder of the rat, and the distribution of dye extravasation was analyzed. c-fos expression within the spinal cord was determined immunocytochemically after chemical irritation of the prostate, bladder and superficial somatic region determined by the dye extravasation as a referred pain area (tail root). Chemical irritation of the prostate resulted in plasma extravasation in L5 to S2 dermatomes (primarily in L6 and S1). In rats receiving bladder irritation, the distribution of plasma extravasation showed a similar pattern to that observed in animals receiving prostatic irritation. Chemical irritation of the 3 structures resulted in expression of c-fos positive cells within the lumbosacral spinal cord. With each treatment the majority of c-fos positive cells were in the L6 and S1 segments. In all 3 groups the highest percentages of c-fos positive cells were observed in deeper laminae, including the dorsal commissure and sacral parasympathetic nucleus. Our results strongly suggest that referred pain status in inflammation of the bladder and prostate is neurogenically mediated. Based on these studies, there should be significant overlaps of nociceptive neurons within the spinal cord, which receive nociceptive inputs from pelvic soma and viscera.

An association between migraine and cutaneous allodynia

Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well-defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation.

An association between migraine and cutaneous allodynia

Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well-defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation. Ann Neurol 2000;47:614–624