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ARTICLE IN PRESS Medical Hypotheses xxx (2009) xxx–xxx

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The other mechanism of muscular referred pain: The ‘‘connective tissue” theory Dong-Gyun Han * Department of Neurolgy, DaeJeon HanKook Hospital, 496-15 SungNam 2 Dong, DaeJeon, ChungCheongNam-Do 300-709, South Korea

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Article history: Received 18 February 2009 Accepted 21 February 2009 Available online xxxx

s u m m a r y Muscular referred pain, that is, pain perceived in a somatic area other than the site of the noxious stimulation, takes place on a specific place to each muscle in constant and predictable pattern. The central hyperexcitability theory focused on spinal cord, the most proper theory at present, can explain well the segmental pattern of referred pain showing delayed onset. But it is hard to explain the non segmental pattern of referred pain areas of superficial-seated or limb girdle and limb muscles. Referred pain areas of limb girdle and limb muscles appear on the skin above a belt of synergistic muscles beyond the segmental areas. In the case of forearm and calf muscles, referred pain shows up on the palm and sole, the point of force application to the outer object. This finding reflects biomechanical relationship between muscle and its referred pain area. From the phylogenetic perspective, aquatic vertebrated animals (e.g. fish) use myoseptum surrounding myomere, connected to skin to keep tensile strength with it for effective swimming. Likewise, in terrestrial vertebrated animals, there are skin parts weakly interconnected with muscles, though the tensile property of nearly all the skin devolutes except the points of action with the outside. These points are dynamic maximal skin tension areas connected with muscles through superficial fascia, in other words, referred pain areas. Referred pain of deep-seated or truncal muscles appears on the trunk segmentally via spinal cord (the central hyperexcitability theory), but superficial-seated or limb girdle and limb muscles elicit referred pain on dynamic maximal skin tension area through connective tissue (the ‘‘connective tissue” theory). Ó 2009 Elsevier Ltd. All rights reserved.

Neurophysiologic aspect To complement the central hyperexcitability theory The convergent-projection theory [1,2] is based on the convergence of visceral and somatic afferent fibers on the same central neuron. The nociceptive activity from viscera is misinterpreted as originating from somatic area, more common sensory input place.

It could explain the segmental nature of muscular referred pain, but it does not explain time delay of referred pain after local pain and different thresholds for eliciting local and referred muscle pain. Also, referred pain does not commonly have bidirectional phenomena of local pain and referred pain because of little convergence of deep and superficial afferents on dorsal horn neuron. Recently, Mense [3] suggested the central hyperexcitability theory.

Convergent connections from deep tissues to dorsal horn neurons are not present from the beginning but are opened by continuous noxious stimuli arising from muscle tissue, and referral to somatic segments is due to central sensitization. This induced hyperexcitability developing on spinal cord can explain the spreading segmental pattern of referred pain of deep-seated or truncal muscles and time delay of referred phenomena easily [3] but can not ex-

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plain the non segmental pattern of referred pain of superficialseated or limb girdle and limb muscles (e.g. latissimus dorsi, trapezius). The hyperexcitability produces complete segmental reflex just like visceral referred pain [4]. Deep-seated or truncal muscles show the segmental nature of referred pain but muscles of neck, limb girdle and limb do not show exactly the segmental pattern of referred pain [5–7]. Muscles of neck, limb girdle and limb need the other mechanism to explain referred pain. And also the central hyperexcitability theory can not explain the decreased intensity of referred pain after completely blocking the afferent nerve from referred pain area [8,9], even though there is no pain reduction of referral point according to this theory. Referred pain of muscles of neck, limb girdle and limb could be primarily peripheral in origin, just like ‘‘barrier–dam” theory [10]. To complement the central hyperexcitability theory, the peripheral hyperexcitability theory is needed.

Biomechanical aspect A dermomyokinetic chain like a myokinetic chain Luigi Stecco [11] demonstrated that each muscle acts together with synergistic muscles connected with fascia to make a myokinetic chain [12]. For example, muscles of antemotion of upper limb which form a myokinetic chain are pectoralis ma-

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jor and minor, coracobrachialis, deltoid, brachialis, biceps brachii, flexor pollicis longus, flexor carpi radialis, and flexor and abductor pollicis brevis in succession. Retromotion of upper limb is composed of rhomboideus major and minor, trapezius, teres major, deltoid attached to the scapular spine, latissimus dorsi, long head of triceps, lateral and medial head of triceps, anconeus, extensor carpi ulnaris, extensor digitorum, abductor digiti minimi and extensor digiti minimi. A myokinetic chain of lateromotion of upper limb has omohyoid, scalenus, deltoid, supraspinatus, long head of biceps, brachioradialis, extensor carpi radialis longus, dorsal interossei, and abductor pollicis longus.

Referred pain areas of pectoralis major, supraspinatus and latissimus dorsi muscles appear on the skin above the functional group of synergistic muscles in a myokinetic chain, though they must develop on only the segmental areas corresponding to muscle innervations, satisfied with the central hyperexcitability theory. Why do referred pain areas of these muscles develop and spread in line with the functional muscle units ‘‘beyond the segmental areas”? This finding suggests that referred pain areas are arranged to their own function, dependent on muscles at the same time. If there is a function, there will be the structure according to it. Referred pain areas could have their own structure, but the structure to be inseparably related with muscle, because they are evolving from the same function. Muscles of forearm and calf make referred pain on the palm and sole, places on which most all the forces of our body are exerted.

This finding is certainly suggestive of structural relationship between muscle and its corresponding referred pain area. Tensile strength is working between them. Skin part under tension developed during muscle contraction is referred pain area (tensile pattern of referred pain area). Just as making arrangement of collagen fibers of bones and ligaments in parallel to tension lines, it is possible to form tensile arrangement of collagen fibers between muscle and its referred pain area even if only during muscle contraction. Force of muscle is transmitted to bone through ligament but for the effective muscle contraction, muscle needs a point of force application which must have a mechanically-stabilized area, not easily stripped off, as we use a tight-fitting glove to work more efficiently. Muscle, deep fascia, superficial fascia and dermis are under the dynamic tension, however not strong because loose connective tissue holds superficial fascia and further, a dermomyokinetic chain consisting of them could be made exactly like a myokinetic chain.

Phylogenetical aspect A vestigial remnant of myoseptum?

Aquatic vertebrated animals such as fish need interconnection between integument and myomere by myoseptum for effective swimming. But terrestrial vertebrated animals adapted to air environment need not have strong connection within them like a fish because they made the transition from axially-powered swimming to appendicularly-powered, terrestrial locomotion [13,14]. Though tensile structure between skin and muscle regressed to be weak and function of most of skin absorbs or disperses an external shock(viscoelastic property), some part of skin, especially palm and sole which contact with object and ground directly became stronger (tensile property). Palmar and plantar aponeuroses are the structure to adapt to strong tension between skin and muscle.

If we image that we are crawling underwater like an aquatic animal, we could think of maximal tension areas of each muscle interacting with water. An interconnecting structure between muscle and its referred pain area could be a vestigial remnant of myoseptum of fish.

Ontogenetical aspect Against the rule of segmentation In the early embryo stage, progenitor cells of dermis and muscle originate and migrate from dermomyotome. Though connective tissue is interposed between dermatome and myotome later, development of dermis and muscle is closely linked together [15,16]. Truncal and deep-seated muscles around vertebrae have segmental innervations from spinal nerves from the embryo stage to the adult stage. On the contrary, muscles of limb girdle or limb have no more pure segmental pattern because of making mixed somites to fulfill complex muscle action. Skin develops like muscle in the same way. Referred pain areas of intercostalis or multifidi and rotators muscles have the segmental pattern just like visceral referred pain but referred pain areas of superficial-seated or limb girdle and limb muscles do not follow dermatomal, myotomal or sclerotomal pattern exactly [16]. Muscular referred pain areas are skin too. Why do not referred pain areas follow the segmental pattern? Referred pain areas are not pure segmental or mixed segmental on limb girdle and limb. They are against the rule of segmentation. All the derivates of each somite are under the same innervations of spinal cord. Referred pain areas of superficialseated or limb girdle and limb muscles are not in the control of spinal cord. This means that referred pain areas are not spinal cord-centered areas but independent structures having their own function.

Inman and Saunders [18] found that noxious stimulation of deep-seated muscles, ligament and periosteum produced the segmental (sclerotomal) pattern of referred pain area. And Travell and Bigelow observed referred pain areas of some muscles did not follow a simple ‘‘segmental” pattern [6].

Histologic aspect Connective tissue inducing the non segmental referred pain Superficial fascia contains fatty tissue and serves to anchor the skin to the underlying tissues making skin tension lines, e.g. Langer’s line [19]. Especially areas such as the scalp, palms, back of the neck have a strong attachment to the underlying tissues. It provides insulation, shock absorption, energy storage, and the ability of skin to slide over joints. Its loose connective tissue surrounds the major blood vessels and nerves of the skin [20]. If mechanical stimulation is given to this tissue, it can give widespread effects on collagen fibers as well as on vascular and neural elements present within this tissue [21]. Loose connective tissue constitutes the collagenous matrix through which immune, endocrine, paracrine signaling molecular exchange take place [22]. Therefore the noxious stimulation of muscle connected with deep fascia and loose connective tissue can transmit signal to vascular and neural cells within this loose connective tissue. So, dynamic skin tension area produced by this tissue on muscle stimulation can produce delayed pain, i.e., referred pain and its tissue trophic changes. The non segmental or tensile pattern of referred pain follows indirect pathway that means signal transmission from connective tissue to nerve.

Experimental studies Evidence of peripheral origin of referred pain Change of blood flow and temperature on referred pain area [23] After injecting hypertonic saline into tibialis anterior muscle, the skin blood flow and temperature were assessed at four different skin area: ipsilateral muscle pain area, ipsilateral referred pain

Please cite this article in press as: Han D-G. The other mechanism of muscular referred pain: The ‘‘connective tissue” theory. Med Hypotheses (2009), doi:10.1016/j.mehy.2009.02.040

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area, and two corresponding areas on the contralateral non-injected leg. The skin blood flow and temperature increased on the injection site, its referred pain area and the corresponding area to the injection site, but the corresponding area of referred pain area of the injection site did not evoke any significant changes in skin blood flow and temperature. This suggests that the corresponding area of referred pain area of the injected muscle does not depend on spinal cord, reflex center of segmental referred pain.

I would like to explain these responses using the ‘‘connective tissue” theory. Responses of ipsilateral muscle pain area and corresponding area of the contralateral non-injected leg are the ‘‘mixed segmental” responses via spinal cord and response of ipsilateral referred pain area is the ‘‘non segmental” response via connective tissue connected to tibialis anterior muscle. It is reasonable that corresponding referred pain area of the contralateral non-injected leg was not evoked because no stimulation was applied to the contralateral tibialis anterior muscle, according to the ‘‘connective tissue” theory. Areas of the ‘‘mixed segmental” response and the ‘‘non segmental” referred pain will be overlapped if more deep-seated or truncal muscles are stimulated.

Experimental trigger point After producing trigger point within extensor digitorum communis by repeated eccentric contraction of the middle finger, when an EMG recording electrode was inserted at the depth of the fascia investing the muscle of tender point, a regular low frequency spike discharge was detected simultaneous with a dull pain sensation of referred pain pattern [24]. This result implies participation of fascia in the development of referred pain.

Block of the afferent nerve from referred pain area The referred pain intensity is somewhat reduced, when myelinated nerve fibers going to referred pain area are blocked completely [8,9]. This means that referred pain depends on intact peripheral nerve, to some degree and need the spontaneous sensory input inevitably [25]. Why does the spontaneous sensory input develop on the innocent referred pain area, remote from the criminal muscle? The mechanism of the spontaneous sensory put is peripheral sensitization through connective tissue, as described above. If we study referred pain area carefully, some parts of a referred pain area carry the segmental pattern, the other parts carry the tensile pattern within a muscle (e.g. latissimus dorsi, levator scapulae muscle) [17]. This is why some degree of reduction of referred pain develops. Most of all the muscles have the mixed pattern of referred pain, undoubtedly the more ‘‘superficial-seated, away from the trunk” muscles are situated, the more ‘‘peripheral” origin of referred pain is.

Clinical experience We know well that doing trigger point injection or Gunn’s intramuscular stimulation in a painful muscle causes a local twitch response and radiation of pain toward its referred pain area [17,29]. Radiating sensation from trigger point to referred pain area is similar to a radiculopathy caused by burging disc?

There is no peripheral nerve that innervates an involved muscle and its exact referred pain area simultaneously on limb girdles and limbs. There is no peripheral nerve showing one-to-one correspondence between them on limb girdles and limbs. It is hard to explain this spreading phenomenon using the central hyperexcitability or the ‘‘barrier–dam” theory, although it is more close to peripheral origin of referred pain. This phenomenon is compatible with the ‘‘connective tissue” theory, in other words, there is the existence of an interconnecting structure between muscle and its referred pain area.

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Evolutionary standpoint Referred pain as a defense measure of muscle The unpleasantness of pain encourages organisms to use any means at its disposal to disengage from the noxious stimuli that cause the pain. Pain can prevent further damage from occurring and promote the healing process as most organisms will protect an injured area from further damage in order to avoid further pain [26,27].

Diseased internal organs make referred pain on the body surface and protect themselves from the exterior impact. Muscle spasm, hyperalgesia and increased sudomotor and sebaceous gland activity on referred pain area would keep away from painful stimuli and decrease friction on the body surface by producing sweat and sebum in order to disperse the outer force. Muscular referred pain also stops activity of injured muscles and protects them from further damage by producing hyperalgesia and autonomic concomitants on application point of muscle force, exactly maximal skin tension point.

Because biological evolution follows economic efficiency, that is the utility-maximizing effort [28], internal organ and deep-seated muscle near the spinal cord induce referred pain on the trunk and muscles of limb girdle and limb remote from the spinal cord induce referred pain on their own position, not using the spinal cord. Each muscle solves its own problem on its own place.

Conclusion The most reasonable mechanism to explain muscular referred pain at present is the central hyperexcitability theory. This mechanism explain delayed onset of segmental pattern of referred pain and its autonomic concomitants through central sensitization very well. But even the central hyperexcitability theory can not suggest plausible rationale for the non segmental pattern of referred pain and reduction of referred pain intensity after complete block of afferent nerves from referred pain area. To solve these problems, I invented the ‘‘connective tissue” theory from biomechanical and phylogenetic perspectives. Muscular referred pain areas that show the non segmental pattern are biomechanically dynamic maximal skin tension areas produced by not so strong interconnection between skin and muscle and phylogenetically points of force application to the exterior. Muscular referred pain areas are pathologic expression of injured muscle on the skin through indirect pathway that superficial fascia between skin and muscle elicits change of nerves and vessel going to referred pain area. Origin of referred pain of superficial-seated or limb girdle and limb muscles is more peripheral. On the contrary, origin of referred pain of deepseated or truncal muscles is central just like visceral referred pain.

There are no superficial-seated muscles that show purely segmental or non segmental pattern of referred pain. Nearly all the referred pain areas of superficial-seated muscles show mixed pattern. This finding can explain reduced referred pain intensity after completely blocking afferent nerves from referred pain area.

The ‘‘connective tissue” theory complementary to the central hyperexcitability seems like the ‘‘barrier–dam” theory in peripheral origin of referred pain but unlike in focusing on connective tissue, not peripheral nerve. It could be possible to demonstrate that dynamic maximal skin tension area induced by muscle contraction is muscular referred pain area by using skin tension meter in future.

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