This survey has presented key issues within sensory manifestations of muscle pain with a focus on (i) the sensory modalities relevant for muscle nociception, (ii) referred muscle pain, referred hyperalgesia, and (iii) deep tissue hyperalgesia in acute muscle pain conditions. The peripheral apparatus of muscle pain consists of nociceptors that can be excited by algesic substances and external nociceptive stimuli. Histologically, the nociceptors are free nerve endings supplied by group III (thin myelinated) and group IV (non-myelinated) afferent fibres with conduction velocities below 30 m/s. The nociceptive muscle afferent fibres terminate in lamina I and V of the dorsal horn or in the subnucleus caudalis in the brain stem. The majority of second-order neurones receive multi-tissue convergence. Similar to cutaneous nociception, the fibres of second-order neurones processing muscle nociception proceed mainly via the spinothalamic tract to the thalamus and further to a network in the cerebral cortex. Algesic substances (e.g. hypertonic saline, acidic buffers, capsaicin, bradykinin, serotonin, glutamate, potassium chloride), ischaemic exercise, powerful exercise, and external stimuli (e.g. mechanical, thermal, and electrical) have been shown to induce muscle nociception in animals and muscle pain in humans. Stimulus intensity (i.e. strength, volume, concentration) and temporal and spatial summation are the main determinants of the muscle pain sensation. In the present studies new models of experimental muscle pain have been developed, applied, and refined. Mechanisms involved in experimental pain induced by hypertonic saline (I, II), ischaemic contractions (II), and mechanical (III) and thermal (IV) stimulation have been explored and confirmed the mechanical, chemical, and thermal modalities known from animal studies. For the first time thermally induced muscle pain and a non-painful pressure sensation from deep tissue in humans have been reported. The impact of thermally induced muscle pain (IV) needs further investigations but there are indeed relevant clinical conditions with increased tissue temperature and deep tissue pain such as localized inflammatory reactions, exercise-induced pain, and fever. The neural apparatus for the non-painful mechanosensation from muscle (III) may potentially be facilitated and be of relevance in hyperaesthetic deep tissue conditions. Referred pain is perceived at a site adjacent to or at a distance from the site of origin. Muscle pain evokes referred pain that typically is felt as a deep sensation, delayed compared to the muscle pain, inhibited over time with constant muscle pain (VI, VIII) and is correlated to the local muscle pain intensity. Somatosensory afferent activity from the referred pain area is not a necessary condition for referred pain (V). Referred deep tissue hyperalgesia has been reported previously, especially in soft tissue referred pain areas, in contrast to the decreased sensitivity of deep tissue in referred pain areas including hard tissue such as joint or bone (VI-VIII). Increased sensitivity of soft tissue adjacent to areas of referred pain has been found (VIII). Referred cutaneous hyperalgesia to natural stimuli is not frequent (VII, VIII). Convergent afferent inputs from the skin, muscles, joints, and viscera on second-order neurones are numerous and may cause misinterpretation of the information coming from muscle afferent fibres when reaching higher levels in the central nervous system, and hence be one reason for the diffuse and referred characteristics. Under normal conditions, afferent fibres have functional synaptic connections with second-order neurones as well as latent synaptic connections to other neurones in the spinal cord or brain stem. Following ongoing strong noxious input, latent synaptic connections become operational, thereby allowing for convergence of input from more than one source. In the context of referred pain, the unmasking of new receptive fields due to central sensitization could mediate referred pain and referred hyperalgesia. Descending inhibitory control systems may act specifically on the neurones involved in the mediation of referred pain and explain inhibition of referred pain over time (VI) and decreased sensitivity in the referred pain area (VI-VIII). The present studies have contributed to a proposed model of referred pain by providing new knowledge on the involvement of peripheral afferent input from the referred pain area (V), temporal aspects of local and referred pain (VI), and referred sensitivity changes (VI-VIII). Competing central excitatory and inhibitory mechanisms, combined with receptor accessibility in the referred pain area, might explain the diverse findings of referred sensitivity changes. The mechanism for acute referred pain, including its neural plasticity, is probably fundamental in the pathophysiological sequelae involved in chronic widespread musculoskeletal pain conditions. Experimental muscle pain leads to a variety of changes in deep and superficial tissue sensitivity in the local muscle pain area. In previous studies homotopic hyperalgesia and hypoalgesia have been reported to occur in both superficial and deep structures, during and/or after pain, and at or adjacent to the injection site for hypertonic saline. In this review neurophysiological models based on sensitization and/or desensitization of receptors or central neural structures are proposed to be involved in the variety of changes in the somatosensory sensitivity after experimental muscle pain. Factors such as stimulation intensity, area, receptor specificity, and potential tissue damage resulting in the release of sensitizing substances may influence the balance between the involved mechanisms. In the present studies (II, IV, VI, IX) the somatosensory sensitivity changes were assessed locally after salineinduced muscle pain by controlling factors (e.g. influence of skin sensitivity, injection procedure, and pain intensity) contributing to the variable effects on deep and superficial sensitivity. The injection procedure and sensitivity assessment by pressure stimulation can in fact cause deep tissue hyperalgesia (IX). However, deep tissue hyperalgesia is not a consistent finding in saline-induced muscle pain (IV, VII), indicating that the clinical deep tissue hyperalgesia is not likely to be explained by the simple peripheral effects after acute muscle pain. In some cases deep tissue hyperalgesia adjacent to the pain locus is correlated to the pain intensity (II), indicating that central summation or sensitization might be involved. The manifestations of prolonged (days) experimental muscle pain on deep tissue sensitivity are not known and time may be found to be the main determinant of the balance between peripheral and central sensitizing processes. The improved understanding of muscle pain mechanisms linked to referred pain, referred hyperalgesia, and deep tissue hyperalgesia will be crucial in developing more rational diagnostic and treatment strategies. For example, based on the experimental methods included in this survey, facilitated referred pain mechanisms were detected in chronic musculoskeletal pain patients (see section 3.1.1) and analgesic efficacy screening of pharmacological interventions was achieved efficiently in patients (159, 184). Further experimental and clinical studies are needed to improve diagnostic and intervention strategies. © 2006 Taylor & Francis on license from Scandinavian Rheumatology Research Foundation.
