Pathophysiology of muscle pain

Siegfried Mense, Department of Anatomy and Cell Biology III, Heidelberg University, D-69120 Heidelberg, Germany

Peripheral mechanisms

Local pain from muscle is due to the excitation of muscle nociceptors by overuse, trauma, or inflammation. In this type of pain, many substances are involved that are released from the damaged tissue (e.g. potassium ions, prostaglandin E2, bradykinin, serotonin) or from the nociceptive nerve ending (e.g. neuropeptides such as substance P (SP), calcitonin gene-related peptide (CGRP) or somatostatin (Mense, 1997 ; Molander et al., 1987). Microneurographic recordings in volunteers showed that the responses of human muscle nociceptors to injections of algesic substances were very similar to those of nociceptors in rat or cat (Marchettini et al., 1996). A substance of particular interest for muscle pain is adenosin triphosphate (ATP) which is present in muscle cells in high concentration. Following a physical muscle lesion, ATP is released from the muscle cells and, therefore, might constitute a stimulus that is specific for muscle pain.

At high concentrations, the substances released from muscle tissue are able to excite nociceptors directly ; at low concentrations they sensitise the receptors (Mense, 1981). A sensitised nociceptor lowers its normally high excitation threshold into the innocuous range and can be activated by weak innocuous stimuli. The tenderness and pain during movement of a damaged muscle is mainly due to the low threshold of sensitised muscle nociceptors. Contrary to former belief the sensitisation is not an unspecific effect – e.g. due to a structural lesion of the receptor - but caused by binding of the sensitising substance to a specific receptor molecule in the membrane of the nociceptive ending (Kidd et al., 1996 ; Cesare and McNaughton, 1997). There is evidence in the literature showing that the structure of the molecular receptor for bradykinin changes in the course of an inflammation.

A question of considerable practical interest concerns the presence of tetrodotoxin (TTX)-resistant sodium channels in the membrane of afferents from muscle. These ion channels are assumed to be specific for nociceptive fibres (Akopian et al., 1996), but nothing is known about their presence in muscle afferents. Preliminary evidence from our laboratory indicates that afferent fibres from muscle nociceptors possess TTX-resistant sodium channels. Fibres of this type appear to be quite numerous in a muscle nerve ; therefore, an input via these fibres to the spinal cord is likely to have strong effects.

During longer-lasting lesions of muscle such as an inflammation, the density of nerve endings that can be visualised with antibodies to SP and nerve growth factor (NGF) has been shown to increase (Mense et al., 1998). The higher numbers of NGF-containing fibres suggest that the increased density is not simply due to an increased concentration of SP in preexisting nerve endings but reflects a true sprouting of receptive endings. The increased density of SP-containing fibres – most of which are assumed to fulfill nociceptive functions - may contribute to the hyperalgesia of a chronically altered muscle, because in a muscle with a higher density of nociceptive fibres a noxious stimulus will activate more endings and, therefore, will elicit more pain.

Spinal mechanisms

Many types of muscle pain have a tendency to be referred, i.e. the pain is felt at sites remote from the lesion. The referral leads to a mislocalisation of the pain by the patient. For instance, the pain that is referred from myofascial trigger points in neck muscles is often felt in the temporal muscle and the forehead (Travell and Simons, 1983). This may lead to the false diagnosis of tension-type headache. One possible mechanism explaining the referral of muscle pain is an expansion of the spinal neuronal population that can be excited by input from the damaged muscle. Results from experiments on rats with an inflammation of a hindlimb muscle suggest that the expansion is brought about by the opening of “silent” (ineffective) synapses in the spinal cord by a longer-lasting nociceptive input from muscle (Hoheisel et al., 1994). This mechanism may lead to a situation where trigeminal neurones in the brainstem that mediate pain from the forehead can be activated by input from nociceptors in neck muscles, and the patients feel (additional) pain in the forehead. Among the substances that have been shown to induce an expansion of the neuronal population that responds to a given input are SP acting on NK-1 and glutamate acting on NMDA receptors (Woolf and Thompson, 1991).

The lesion-induced expansion of the spinal target area of a peripheral nerve is probably due to a central sensitisation, i.e. an overexcitability of dorsal horn neurones which under these circumstances respond to an input that normally does not affect these cells. Recent evidence from clinical investigations shows that the pattern of referral is altered in patients with chronic muscle pain, e.g. in fibromyalgia (Graven-Nielsen et al., 1999). Besides pain referral, spread of pain and hyperalgesia in patients are other phenomena that are assumed to be due to central sensitization.

After induction of an experimental myositis there is a relatively narrow time window during which the pathological afferent input induces central sensitisation. A local anaesthetic block of the muscle afferents within the first two hours of the inflammation prevented the central sensitisation for at least 8 hours, but a later block (2 to 4 hours after induction of the myositis) had no influence on the development of the central sensitisation (Hoheisel et al., 1997a). These data underline the importance of an early and effective analgesic therapy for the prevention of central hyperexcitability in patients.

A novel substance probably involved in the development of spontaneous pain - particularly chronic pain - is nitric oxide (NO). Nitric oxide is synthesised by neurones and other cells that contain the enzyme NO synthase (NOS). Normally, the local release of NO in the spinal cord inhibits the resting activity of nociceptive neurones. (This local antinociceptive action of NO has to be distinguished from its pronociceptive, hyperalgesic, action which is probably due to the action of NO on supraspinal centres and descending pathways. The nociceptive input from a chronic muscle lesion causes a reduction in the number of neurones that possess the enzyme for the synthesis of NO. The associated decrease in the local NO concentration disinhibits nociceptive neurones which develop increased resting activity (Hoheisel et al., 1995). Increased activity in nociceptive neurones causes spontaneous pain in patients.

Electrical stimulation of primary afferent fibres at various intensities and frequencies, and for various durations showed that increased activity in each fibre type (AЯ-, Aю-, C fibres) is followed by changes in the numbers of NO-synthesising neurones in the dorsal horn (Hoheisel et al., 1997b). However, only activation of C fibres lead to a new synthesis of NOS as evidenced by an increase in nNOSmRNA in the cells. This increase in mRNA was present not only on the side ipsilateral to the stimulation but also in the contralateral dorsal horn. This latter finding of bilateral central nervous changes caused by a unilateral input may be of clinical importance, because it could give an explanation for symmetrical pains such as occur in rheumatoid arthritis and fibromyalgia.


Cesare P, McNaughton P (1997) Peripheral pain mechanisms. Curr Opin Neurobiol 7 : 493-499.
Graven-Nielsen T, Sorensen J, Henriksson KG, Bengtsson M, Arendt-Nielsen L (1999) Central hyperexcitability in fibromyalgia.
J Musculoskel Pain 7, 261-271.
Hoheisel U, Koch K, Mense S (1994) Functional reorganization in the rat dorsal horn during an experimental myositis. Pain 59, 111-118.
Hoheisel U, Sander B, Mense, S (1995) Blockade of nitric oxide synthase differentially influences background activity and electrical excitability in rat dorsal horn neurones. Neurosci Lett 188, 143-146.
Hoheisel U, Sardy M, Mense S (1997a) Experiments on the nature of the signal that induces spinal neuroplastic changes following a peripheral lesion. Eur J Pain 1, 243-259.
Hoheisel U, Kaske A, Reinert A, Mense S (1997b) Frequency-dependent expression of diaphorase staining and nNOS-immunoreactivity in rat dorsal horn neurones following C-fibre stimulation. Neurosci Lett 227, 181-184.
Kidd BL, Morris VH, Urban L (1996) Pathophysiology of joint pain. Ann Rheum Dis 55 : 276-283.
Marchettini P, Simone DA, Caputi G, Ochoa JL (1996) Pain from excitation of identified muscle nociceptors in humans. Brain Res 740 : 109-116.
Mense S (1981) Sensitization of group IV muscle receptors to bradykinin by 5-hydroxytryptamine and prostaglandin E2. Brain Res 225, 95-105.
Mense S, Pathophysiologic basis of muscle pain. An update. In : A.A. Fischer (ED.), Physical Medicine and Rehabilitation, Clinics of North America, Myofascial Pain-Update in Diagnosis and Treatment. Saunders, Philadelphia, 1997, 23-53.
Mense S, Hoheisel U, Kaske A, Reinert A (1998) Inflammation-induced increase in the density of neuropeptide-immunoreactive nerve endings in rat skeletal muscle. Exp Brain Res 121, 174-180.
Molander C, Ygge J, Dalsgaard C-J (1987) Substance P-, somatostatin- and calcitonin gene-related peptide-like immunoreactivity and fluoride resistant acid phosphatase-activity in relation to retrogradely labeled cutaneous, muscular and visceral primary sensory neurons in the rat. Neurosci Lett 74 : 37-42.
Travell JG, Simons DG (1983) Myofascial pain and dysfunction. The Trigger Point Manual. Williams and Wilkins, Baltimore, London.
Woolf CJ, Thompson SW (1991) The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation ; implications for the treatment of post-injury pain hypersensitivity states. Pain 44 : 293-299.

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 56 - 57.