René Johannes Laursen

Referred pain as an indicator for neural plasticity

Publisher Summary Pain originating from deep somatic structures and viscera represents a major part of patients pain complaints. The chapter discusses the possible mechanisms underlying referred pain from muscles and viscera. Referred pain has been known and has been used extensively as a diagnostic tool in the clinic. Several theories regarding appearance of referred pain have been suggested, and basically, they state that nociceptive dorsal horn neurons receive convergent inputs from various tissues. In clinical practice, classical signs of viscerally referred pain are (1) the radiating pain in arms, particularly the left arm during angina pectoris, (2) McBurneys sign indicative of appendicitis, (3) superficial abdominal pain from gastric ulcers (4) the pain of cholecystitis, which may radiate to the interscapular area, right scapula, shoulder, or back, and (5) pain from renal and urethral stones referred to the lower back. Referred muscle pain is manifested in somatic structures whereas visceral pain manifests in somatic as well as visceral structures. These manifestations are of significantly clinical importance for the diagnosis of pain pathologies.

The effect of compression and regional anaesthetic block on referred pain intensity in humans

The mechanisms underlying local and referred muscle pain are poorly understood. The aim of this experiment was to determine to which degree referred pain is dependent on peripheral or central mechanisms. This was studied by blocking sensory input from the referred pain area. Intramuscular electrical stimulation in the right anterior tibial muscle induced local muscle pain and referred pain in 12 subjects. Nerve blocks were applied on the lower limb between the local and the referred pain area for 60 min. Three different studies were performed: (1) no nerve block (2) compression block, and (3) compression block combined with intravenous regional anaesthesia. The referred pain intensity was assessed every 5 min. To monitor the blockade of myelinated and unmyelinated nerve fibres, touch, pinprick, position sense and heat and heat-pain detection thresholds were assessed on the dorsal side of the foot every 5 min. A significant reduction in referred pain intensity (40.5%) compared with the control experiment was found after 40 min with the compression ischemia nerve block until release of the tourniquet. In the combined nerve block experiment, a significant reduction of referred pain intensity (38.5%) was seen after 20 min and until the release of the tourniquet. There was no significant difference in the referred pain intensity between the two types of blocks. The present findings suggest that both peripheral and central mechanisms play a role in referred pain and that the myelinated fibres mediate the peripheral component.

The effect of differential and complete nerve block on experimental muscle pain in humans.

We have attempted to examine the nerve fiber population mediating experimentally induced muscle pain in humans. Two established methods induced muscle pain: continuous, intramuscular, electrical stimulation and intramuscular infusion of hypertonic saline. A progressive nerve block was achieved by a combination of compression nerve block and intravenous regional anesthesia. Regular tests of muscle pain intensity were performed during the blocking period of 60 min. At the same time, the blocking of thick and thin afferents was monitored by assessment of proprioception and cutaneous touch, pin‐prick, pressure pain, and heat‐detection thresholds. Electrically induced muscle pain was inhibited (P < 0.0001) in parallel with proprioception, touch, and pin‐prick, which were mediated by thick and thin myelinated nerve fibers. Saline‐induced muscle pain was inhibited (P < 0.002) synchronously with heat detection and pressure pain, which are mediated by unmyelinated nerve fibers. Based on the present psychophysical experiments, it is suggested that: (1) myelinated afferents mediated mainly electrically induced muscle pain, and (2) unmyelinated afferents mediated mainly saline‐induced muscle pain.

Referred pain is dependent on sensory input from the periphery: A psychophysical study

Muscle pain can be characterized by local pain and pain referred to distant somatic structures with concomitant cutaneous and deep somatosensory changes. The mechanisms responsible for referred muscle pain are poorly understood. The aim of this study was to study the origin of experimentally‐induced referred muscle pain by anaesthetizing the skin overlying the referred pain area and to quantify deep somatosensory changes in the area.

Quantification of local and referred pain in humans induced by intramuscular electrical stimulation

The basic knowledge related to referred muscle pain is limited. To study referred pain, an experimental model using intramuscular electrical stimulation has been developed.

Opioid-insensitive hypoalgesia to mechanical stimuli at sites ipsilateral and contralateral to experimental muscle pain in human volunteers

Musculoskeletal pains are often characterised by referred pain and hyperalgesia. The aim of the present study was to examine the sensitivity to pressure and pinprick at sites ipsi- and contralateral to capsaicin-induced pain in the tibialis anterior (TA) muscle. Visual analogue scale (VAS) scores of the sensation to sub- and supra-pain threshold stimuli by pressure and pinprick were recorded before, during and after experimental muscle pain. It was found that pressure stimulation (120% of baseline pain threshold) delivered over the ipsilateral deep peroneal nerve between the 1st and 2nd metatarsal bones showed a significant increase in VAS scores during muscle pain. The referred pain did not overlap this hyperalgesic site. Ipsilateral test sites at the TA muscle, great toe and between the 3rd and 4th metatarsal bones did not show any changes in response to pressure stimulation during pain. In contrast, test sites at the ipsilateral ankle showed hypoalgesia to pressure during muscle pain. In the contralateral leg hypoalgesia to pressure was found at all sites during pain. The decreased sensitivity to pressure was confirmed with both sub- and supra-pressure pain-threshold stimuli. VAS scores to pinprick were either decreased or unchanged during pain compared to before pain. Naloxone administrated in a placebo-controlled manner had no effect on hypoalgesia to pressure or pinprick during muscle pain. Thus, the generalised decreased sensitivity may reflect activation of non-opioid endogenous pain inhibitory systems. The lack of change in sensitivity at some sites could indicate a competitive balance between excitatory and inhibitory mechanisms. The deep peroneal nerve specifically innervates both the TA muscle and the only site of hyperalgesia indicating spatial summation of afferent activity from these structures.

Cripto-1 expression in glioblastoma multiforme

Human glioblastoma multiforme (GBM) is an aggressive cancer with a very poor prognosis. Cripto‐1 (CR‐1) has a key regulatory role in embryogenesis, while in adult tissue re‐expression of CR‐1 has been correlated to malignant progression in solid cancers of non‐neuronal origin. As CR‐1 expression has yet to be described in cerebral cancer and CR‐1 is regulated by signaling pathways dysregulated in GBM, we aimed to investigate CR‐1 in the context of expression in GBM. The study was performed using enzyme‐linked immunosorbent assay (ELISA), Western blotting, polymerase chain reaction (PCR) and immunohistochemistry to analyze the blood and tissue from 28 GBM and 4 low‐grade glioma patients. Within the patient cohort, we found high CR‐1 protein levels in blood plasma to significantly correlate with a shorter overall survival. We identified CR‐1 in different areas of GBM tissue, including perivascular tumor cells, and in endothelial cells. Collectively, our data suggest that CR‐1 could be a prognostic biomarker for GBM with the potential of being a therapeutic target.