Sensory nerve supply in the human subacromial bursa

Sensory nerve supply in the human subacromial bursa Katsuhiko Ide, MD, Yasumasa Shirai, MD, Hiromoto Ito, MD, and Hironobu Ito, MD, Tokyo, Japan

The subacromial bursa is the major component of the subacromial gliding mechanism. The neural elements of the subacromial bursa obtained from specimens that underwent autopsy and surgery were investigated by the silver impregnation and immunohistochemical methods with antisera to substance P and calcitonin gene-related peptide, which are considered to be involved in nociceptive transmission, and protein gene product 9.5. Free nerve endings, Ruffini endings, Pacinian corpuscles, and two kinds of unclassified nerve endings were observed. Most of these receptors were observed at the roof side of the coracoacromial arch, which is exposed to stress because of the impingement. A8 and C fibers, thought to be nerve fibers of free nerve endings, were immunoreactive to substance P and calcitonin gene-related pepfide. On the other hand, thick fibers thought to originate in encapsulated mechanoreceptors were not immunoreactive to substance P. The subacromial bursa receives nociceptive stimuli and proprioception and seems to regulate appropriate shoulder movement. (J SHOULDERELBOWSURG 1996;5:371-82.) The subacromial bursa (SAn), the largest bursa in the human body, r is located under the coracoacromial (C-A) arch and deltoid muscle. The inferior aspect of the SAn contacts the greater tuberosity of the humerus and the rotator cuff muscles. The SAn reduces friction between the rotator cuff muscles and the C-A arch during shoulder movement, and thus the SAn plays a role in lubrication of the shoulder joint. From the clinical point of view when the shoulder is elevated, the greater tuberosity of the humerus passes under the C-A arch, so that the supraspinatus muscle and SAn undergo some amount of friction. Thus the SAn is one of the most important tissues associated with discomfort and restriction of shoulder movement.6, 14, 20, 2 9 In recent years histologic studies have demonstrated that sensory nerve endings such as nociceptors and mechanoreceptors are in the ligaments and joint capsules of the spine and the knee From the Department of Anatomy and Orthopaedic Surgery, Nippon Medical School. Reprint requests: Katsuhiko Ide, MD, Deparlment of Anatomy, Nippon Medical School, Sendagi 1-1-5, Bunkyo-ku, Tokyo 113, Japan. Copyright 9 1996 by Journal of Shoulder and Elbow Surgery Board of Trustees. 1058-2746/96/$5.00 + 0 32/1/74204

joint. The stimuli from these nerve endings allow recognition of nociception as pain and proprioception. Thus the body seems to have a defense system that minimizes abnormal or excessive movement that may produce a joint disorder.* We hypothesized that the shoulder joint also has this defense system and directed our attention to the SAn, which is the main component of the subacromial gliding mechanism and accepts stress by virtue of its anatomic location. Accordingly, we investigated the existence of sensory nerve endings and their distribution with the silver impregnation method. We also used immunohistochemical methods with antisera to substance P and calcitonin gene-related peptide (CGRP), considered to be neurotransmitters or neuromodulators of nociception,7, 11, ~8, 23, 24, 3o and protein gene product 9.5 (PGP 9.5), considered to be a general neural marker. 28' ss, 37

MATERIAL AND METHODS Silver impregnation method. Three whole SAn were obtained at autopsy from a 76-year-old male cadaver, a 52-year-old female cadaver, and a 44-year-old male cadaver whose charts showed there had been no shoulder complications during *References 8, 9, 12, 13, 19, 31, 33, 34, 38-41

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I:Jgure 1 Free nerve ending that formed plexus in roof of C-A arch side of SAB. Thin (1 to 2 ~m in diameter: small arrow) and thick (2 to 3 t~m in diameter: large arrow) nerve fibers can be seen. Arrowheads indicate free nerve endings that did not form plexus. Modified BieJschowsky's method. Bar = 50 t~m. life. The SAB containing the subdeltoid and subcoracoid bursa was resected with a part of the coracoacromial ligament and deltoid muscle. The specimens were immediately fixed with Bodian II solution* for 2 days and were then placed in 10% sucrose solution for 2 days. After freezing was performed with Tissue Tek O.C.T. compounds (Miles, Elkhart, Ind.) in 60 ~ C n-hexane, the serial sections were cut at a thickness of 30 IJm by cryostat and were mounted on slides coated with chromegelatin. A modified Bielschowsky's silver impregnation method was performed as follows: the sections were dipped in 5% formalin for 5 minutes twice, were rinsed with distilled water, were immersed in 17% silver nitrate solution for approximately 1 hour at 40 ~ C, were dipped in 5% formalin, were rinsed with distilled water, were immersed in silver ammonium hydroxide solution for 20 minutes, were dipped in 10% potassium tartrate sodium solution for 1 minute below 4 ~ C, then immersed in the same solution for 10 minutes at room temperature, were rinsed in distilled water, were dipped in tiosulfate sodium for 2 minutes, and were then dehydrated, cleared, and mounted in balsam. After staining was performed, the neural elements of whole SAB were observed under light microscopy. Immunohistochemical method. SAB were *The content of this solution is 90 cc of 80% alcohol, 5 cc of 90% formalin, and 5 cc of glacial acetic acid (D. Bodian, Anal Rec 1936;65:89; Anat Rec 1937;66:153).

obtained from 10 patients (eight men, two women, recurrent shoulder dislocation or proximal humeral fracture) during shoulder operations. The mean age of the patients was 52.8 years (range 21 to 76 years). These specimens were all from the C-A arch side of the SAB. Antisera to substance P (UCB-Bioproducts, Braine-I'Alleud; Belgium), CGRP (Cambridge Research Biochemicals, Wilmington, Del.), and PGP 9.5 (Biogenesis, Bournemouth, England) were used for immunohistochemical detection of the neural elements, and at the same time a modified Bielschowsky's silver impregnation method was carried out for the control group. The specimens were fixed with 4% paraformaldehyde for 2 days and then placed in 20% sucrose solution for 2 days. After freezing was performed with Tissue Tek O.C.T. compounds, serial sections were cut at a thickness of 20 IJm. Every fourth section was mounted on a slide that had been coated with chrome-gelatin for the silver impregnation method, and three adjacent sections were mounted on each series of slides that had been coated with 0.01% poly-blysine (Sigma Diagnostics, St. Louis, Mo.) for the immunohistochemical methods with antisera to CGRP, substance P, and PGP 9.5. The sections for the silver impregnation method were fixed again with Bodian II solution and were then stained by a modified Bielschowsky's silver impregnation method as previously described. Immunohistochemical methods

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Figure 2 Pacinian corpuscle can be observed in adipose tissue. This type of receptor is located in roof of C-A arch side of SAB, showing muhilamellated capsule in which thick axon terminates. Modified Bidschowsky's method. Bar = 50 ~m. with antisera to CGRP, substance P, and PGP 9.5 were used with the avidin-biotin peroxidase complex method ~ as follows. The sections were air-dried for 1 hour and were then treated with 5% normal goat serum (Vector Laboratories, Burlingame, Calif.)in 0.05 mol/L phosphate-buffered saline solution with 0.3% Triton X 100 phosphate-buffered saline solution (PBST) for 1 hour to block nonspecific binding (using avidin/biotin blocking solution produced by Vector Laboratories). The sections were treated overnight with primary antibody diluted in PBST at the following concentrations: CGRP 1:2000, substance P 1:2000, protein gene product (PGP) 9.5 1:5000. This reaction was followed by 1 hour of treatment with 0.5% biotinilated goat anti-rabbit immunoglobulin G (Vector Laboratories) in PBST and 11/2 hours of treatment in avidin biotin reagent (ABC, Vectastain Elite, Vector Laboratories). After each step the slides were washed three times in 0.2 mol/L phosphate-buffered saline solution (pH 7.4) for 10 minutes, and each reaction was

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Figure 3 Ruffini ending on CA arch side of SAB. In thin capsule spray-type nerve fibers enclose and invade bundle of collagen fibers. Modified Bielschowsky's method. Bar = 50 ~m. treated in a humid chamber at room temperature. Visualization was performed by the DAB method intensified with Ni 2§ After washing was done with distilled water, the sections were dehydrated, cleared, and mounted in balsam.

RESULTS Silver i m p r e g n a t i o n . In the SAB, free nerve endings, Pacinian corpuscles, Ruffini endings, and two kinds of unclassified receptors were observed. The free nerve ending is a receptor in which the nerve fiber terminates without a specific capsule. This type of nerve ending was present all over the SAB, and the number was much greater on the side of the C-A arch, where some free nerve endings formed a plexus. The axon diameter of these endings was 1 to 2 pro, but thin axons with a small diameter of 1 to 2 pm and thick axons with a large diameter of 2 to 3 pm were intermingled in the plexus (Figure 1). The Pacinian corpuscle is an ellipsoid-shaped receptor in which the circumference of the nerve fiber is encompassed by a muhilamellated capsule.17, 34, 4 0 These nerve endings were large with

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Figure 4 Unclassified receptors in SAB. A, Elliptic shaped receptor in floor of SAB near greater tuberosity of humerus. There is wide space between thin capsule (arrow) and ramified axon. On morphologic evaluation this receptor is similar to Golgi-Mazzoni corpuscle. B, Small receptor with elliptic capsule in which axon loop terminates. This type of receptor can be observed in adipose tissue of C-A arch side similar to Pacinian corpuscles. Modified Bielschowsky's method. Bar = 50 ~m.

Figure 5 Nerve fiber bundle entering SAB from coracoacromial ligament. Modified Bielschowsky's method. Bar = 50 ~m. a maximum diameter of 450 to 500 IJm, and the axons were 5 to 6 IJm in diameter. The Pacinian corpuscles were localized in the roof of the C-A arch side of the bursa. In addition, it was observed that every Pacinian corpuscle was buried in subsynovial adipose tissue (Figure 2).

The Ruffini ending is fusiform in shape, and the spray-type terminal of the nerve fibers encloses and invades a bundle of collagen fibers within a thin capsule. 34" 4o The Ruffini endings were observed near the greater tuberosity of the humerus and the C-A arch. This type of receptor was ob-

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acromion

4-

greater~ tuberosity

1p

~

,, oraco process

Figure 6 Schematic drawing of major nerve fiber bundles and distribution of sensory nerveendings at SAB. Double circles indicate Paciniancorpuscles. Filled circles indicate Ruffini endings. Asterisks indicate free nerve ending plexus. Hatched areas indicate areas where cluster of Golgi-Mazzoni corpuscle-like receptors exists. White circles indicate type II unclassified receptors. served in the floor side of the SAB near the greater tuberosity, whereas at the C-A arch side these receptors were observed in the roof. The maximum diameter of the Ruffini endings was 100 to 200 iJm, and the axons were 4 to 5 tsm in diameter. Unlike the Pacinian corpuscles, the Ruffini endings were present in subsynovial fibrous tissue (Figure 3). Unclassified receptors in the SAB were divided into two types (Figure 4). The first type (type I) was oval (100 to 200 tJm in maximum diameter) and encapsulated, with short irregular branches ramifying within the capsule (Figure 4, A). A wide space was seen between the nerve fiber and the capsule, and the space appeared to be filled with a transparent substance. The axon of this type of ending was 1.7 to 2.1 tJm in diameter. These receptors were distributed in clusters of corpuscles. These morphologic properties resembled those of the Golgi-Mazzoni corpuscle. This type of ending

was observed in the floor side of the SAB near the greater tuberosity of the humerus. The second type of unclassified receptor (type II) was small, elliptic, and 50 to 100 iJm in maximum diameter. Within the thin capsule the nerve fiber terminated by spirally coiling and looping (Figure 4, B). The diameter of the axon was 2 to 3 IJm. Like the Pacinian corpuscles, this type of ending was observed in subsynovial adipose tissue and distributed in the roof side of the SAB near the C-A arch. Nerve fiber bundles were observed to take a network-like course while bifurcating into a complicated form and finally terminating as nerve endings. All of these endings were present in the subsynovial tissue of the bursa. Most nerve fiber bundles were observed to run predominantly at the edge of the bursa and especially in the vicinity of the C-A arch and the greater tuberosity of the humerus. We found nerve fiber bundles entering

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Figure 7 Extremelythin nerve fibers (arrow) closely encircling blood vessel (V). A, Modified Bielschowsky's method. B, Nerve fibers are immunoreactive only to PGP 9.5. Bar = 50 ~m. the SAB from a side of the coracoacromial ligament (Figure 5) and greater tuberosity of humerus. Some nerve fiber bundles entering from the side of the greater tuberosity of the humerus ramified and terminated in the deltoid muscle as a motor end plate. With serial sections major nerve fiber bundles were traced from the roof to the floor side of the SAB on a two-dimensional plane by camera lucida drawings. In the direction from l 1-o'clock to 4-o'clock of Figure 6, the coracoacromial ligament is present, and the lower left side corresponds to the greater tuberosity of the humerus. The arrow shows the stump of the nerve fiber bundle that has entered the SAB. Immunohistochemistry. In all specimens nerve fibers that were immunoreactive to substance P, CGRP, or PGP 9.5 were observed and compared with silver impregnated sections. All neural fibers were immunoreactive to PGP 9.5. Silver impregnated nerve fibers and endings were classified into three types according to their immunoreactivity to these antisera. The first type of nerve element was immunoreactive only to PGP 9.5, the second type was immunoreactive to both PGP 9.5 and CGRP, and the third type was immunoreactive to PGP 9.5, CGRP, and substance P. In the nerve fibers that showed immunoreactivity to PGP 9.5 alone, we observed nerve fibers run-

ning in close contact with and encircling the blood vessel wall and others running a free course independent of the blood vessels. The former fibers were extremely thin, less than 1 IJm in diameter, and had bulbous swellings along their course (Figure 7). On the other hand, the latter fibers were more than 2 IJm in diameter and were considered to originate in mechanoreceptors. Figure 8 shows a Ruffini ending that was confirmed from the silver impregnated section. Although it was immunoreactive to PGP 9.5, it failed to show any immunoreactivity to CGRP or substance P. The nerve fibers immunoreactive to both PGP 9.5 and CGRP were 2 to 3 iJm in diameter and free from blood vessels. Figure 9 shows a type of unclassified receptor whose axon terminated by spirally coiling and looping in a small elliptic capsule. These nerve fibers were not immunoreaclive to substance P but were immunoreactive to CGRP. The nerve fibers immunoreactive to PGP 9.5, CGRP, and substance P were thin A8 or C fibers. Some of these thin fibers ran adjacent to the blood vessel wall, whereas others ran independently of the course of the blood vessels. However, the thin fibers that ran adjacent to the blood vessel wall did not run as close to the vessel wall as the fibers demonstrating immunoreactivity to PGP 9.5 alone (Figure 10).

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Figure 8 Ruffini ending in SAB stained by modified Bielschowsky's method (A). Axons of Ruffini ending are neither immunoreactive to CGRP (B) nor substance P (C). Axons of this receptor are immunoreactive only to PGP 9.5 (D). V, Blood vessel. Bar = 50 ~m. The sensory nerve elements in the SAB and their morphologic and immunohistochemical properties are shown in Table I.

DISCUSSION In general, bursae are placed between a number of different structures such as skin, tendon, and bone. Similar to the synovial membrane of diarthrodial joints, the bursa is composed of two layers. The inner lining consists of one or several cell layers of synovial cells. Beneath this layer there is

a connective tissue layer consisting of areolar, fibrous, and adipose tissue. Because of these anatomic and histologic features, the bursa has the role of facilitating gliding of one musculoskeletal structure on another. "~' 21 The SAB exists mainly between the C-A arch and the rotator cuff muscles. It has the role of supporting smooth movement of the shoulder joint by reducing friction that occurs in the previously described tissues, especially when the humerus is abducted or elevated. With the recent development in staining meth-

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Figure 9 Small elliptic shaped unclassified receptor (type II) stained by modified Bidschowsky's method (A). Axons of this type of receptor are immunoreactive to CGRP (B) and PGP 9.5 (r Bar = 50 u,m. ods for nerve fibers, many authors have reported identifying sensory nerve endings in the ligaments and joint capsules near the spine and the knee joint in cats and humans.* Wyke 38 classified sensory nerve endings in articular tissue into four types as follows. He described type I receptors as Ruffini type receptors, type II receptors as lamellated (Paciniform) receptors, type III receptors as Golgi tendon organ receptors, and type IV receptors as free, unencapsulated terminals. Furthermore Rowinski 31 added Golgi-Mazzoni corpuscles *References8, 9, 12, 13, 19, 33, 34, 39-41.

to Wyke's classification. He stated that this neural information derived from these nerve endings must serve to (1) protect the joint from being damaged by movement in excess of its normal physiological range, (2) determine the appropriate balance of synergistic and antagonistic forces, that is, muscular action, necessary for smooth joint movement so that voluntary actions may be accomplished, and (3) participate with other proprioceptive afferent receptors from the tendons and muscles in generating a somatosensory image within the central nervous system. We confirmed the presence of nerve endings such as the Ruffini endings, Pacin-

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Figure 10 Bundle of nerve fibers stained by modified Bielschowsky's method (A). In this bundle only thin fibers (arrow) are immunoreactive to CGRP (B) and substance P (C). On the other hand, both thin and thick fibers are immunoreactive to PGP 9.5 (D). V, Blood vessel. Bar = 20 ~,m. ian corpuscles, Golgi-Mazzoni corpuscle-like receptors, and free nerve endings in the SAB. The Ruffini ending is a low-threshold, slowly adapting mechanoreceptor that appears to be stimulated by displacement of collagen fibers in which its nerve fibers intertwine. It has been reported that in cat knee capsule, this receptor is sensitive to the capsule stresses or strains. 12 The Ruffini ending signals the joint position and velocity of joint movement. The Pacinian corpuscle is a dynamic, rapidly adapting mechanoreceptor with a low threshold that signals joint accelerations and decelerations. By deformity of the multilaminated capsule, the

Pacinian corpuscle responds to mechanical displacement resulting from pressure and vibration. 4~ The Golgi-Mazzoni corpuscle is a slowly adapting mechanoreceptor that is sensitive to compression in a plane perpendicular to the plane of the capsule. 13 Regarding the kinetics of the SAB in relation to shoulder joint movement, Birnbaum and Lierse 3 reported that this bursa is connected to the corner of the acromion, that the basal section (or the floor) of the bursa lying directly on the supraspinatus tendon does not shift, and that the roof side of the bursa between the acromion and greater tuberos-

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Table I Sensory nerve endings in the subacromial bursa

Receptor Pacinian corpuscle Ruffini ending Unclassified receptors Type l Type II Free nerve ending Single Plexus

Maximum diameter (l~m)

Axon diameter (~m)

Distribution (at the side of)

Substance P

CGRP

PGP 9.5

450-500 100-200

5.0-6.0 4.0-5.0

C-A arch C-A arch, greater T

H

H

H

100-200 50-100

1.7-2.1 2.0-3.0

Greater T C-A arch

H

(§

(+)

1.0-2.0 1.0-3.0

All areas C-A arch, greater T

(+)

(+)

(+)

Immunoreactivity

C-A arch, Coracoacromial arch; greater T, greater tuberosity of the humerus.

ity of the humerus is bent to deformity at abduction of the shoulder joint. From our study we demonstrated that nerve fiber bundles enter from both sides of the coracoacromial ligament and the greater tuberosity and indirectly confirmed that at least these two sites are fixed. On movement of the shoulder joint forces of stretch and shrinkage always act around these two fixed sites. Moreover, when the upper arm is elevated or abducted, the bursa is impinged between the humeral head and the C-A arch together with the rotator cuff muscles, thus giving rise to a compression force in that region. The Ruffini endings, present at the side of the C-A arch and greater tuberosity in the SAB, were considered to transmit information on shoulder joint position to the central nervous system in response to stretching. The Pacinian corpuscles and Golgi-Mazzoni corpuscles-like receptors, present at the side of the C-A arch and at the side of the greater tuberosity, respectively, are considered to recognize compression caused by the greater tuberosity and C-A arch at the time of elevation or abduction of the upper arm. It has been reported that when the upper arm is elevated, the rotator cuff muscles and the long head of the biceps brachii tendon have to compress the humeral head toward the glenoid to prevent upward subluxation of the humeral head caused by action of the deltoid muscle. We speculated that the mechanoreceptors of the SAB signal the information necessary to control the balance between the muscle strength needed to elevate the upper arm and the muscle strength needed to compress the humeral head toward the glenoid by receiving the angle of the shoulder joint elevation and compression created between the humeral head and the C-A arch.

Detailed reports about the innervations of the SAB are limited in number, but the general view is that they are innervated by the suprascapular nerve. Gardner 1~ stated that the coracoacromial ligament is innervated by the suprascapular nerve. The nerve fiber bundles entering the SAB from the coracoacromial ligament are thought to participate in this nerve. However, we observed entrance of nerve fiber bundles from the greater tuberosity of the humerus, and some of these fibers bifurcated to terminate in the deltoid muscle as motor end plates. Because the deltoid muscle is innervated by the axillary nerve, it is evident that the SAB is innervated by at least two nerves: the suprascapular nerve and the axillary nerve. We hypothesized that the SAB not only serves as a lubricator but also is closely related to the synergistic movement of the shoulder joint because of the reflex arc consisting of the suprascapular and axillary nerves, which conduct proprioception by signaling from the mechanoreceptors in the subsynovial connective tissues. Substance P is a polypeptide consisting of 11 amino acids. It is predominantly contained in small cells of the dorsal root of the spinal ganglion. 5 It is also included peripherally in thin A~ and C fibers3~ and is said to be a neurotransmitter or modulator for nociceptive stimuli. 7' 18, 24 Some investigators have reported that it exists in thin nerve fibers with a diameter of less than 1 tsm in the posterior longitudinal ligament and intervertebral disk in the spine, suggesting that these tissues can constitute a source of low back painT' 22 In this study we confirmed that among the nerve fibers in the subacromial bursa, substance P exists especially in the thin A8 and C fibers from the free nerve endings. The thick nerve fibers originating from the Ruffini

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endings and presumably from encapsulated nerve endings such as the Pacinian corpuscles or others were not immunoreactive to this peptide. CGRP is a neuropeptide that consists of 37 amino acids 1 and has been reported to coexist with substance P. It has been proposed that CGRP is also related to nociception. ~7, 23, 3o This peptide is present not only in small cells but also in large cells of the spinal ganglion. In peripheral nerves CGRP is said to be present in more nerve fibers than substance p.~l It also appears that CGRP is included in nerve fibers transmitting both nociceptive and proprioceptive stimuli. Our results showed the presence of AcS and C fibers, which were immunoreactive to both CGRP and substance P. However, the nerve fibers originating from the Ruffini endings were not immunoreactive to CGRP. This finding suggests that CGRP is not related to the proprioception received by the Ruffini endings. We observed CGRP-immunoreactive nerve fibers originating from one of the unclassified encapsulated endings, but these fibers were not immunoreactive to substance P. Because such endings were observed in silver impregnated sections of the whole bursa to exist at the side of the C-A arch where impingement occurs, we suggest that they may receive mechanical stimuli serving as nociceptive stimuli. Substance P has effects on vasodilatation and vascular permeability7 s' 27, s2 According to Holzer, ~s a close relationship of tachykinins such as substance P is implicated in the development of the flare response caused by an axon reflex in dermal tissue. In other words, part of the nociceptive impulses from the nociceptive stimuli-damaged skin to the spinal cord is antidromically conducted by the branches and reaches nerve endings in the vicinity of the damaged area. After neuropeptides such as substance P are released to increase vasodilation and vascular permeability, the chemical mediators of inflammation appear to produce primary hyperalgesia. Levine et al. 2r have suggested that the release of substance P induced by such an axon reflex may also occur in arthritis. In this investigation among the thin nerve fibers that had a diameter of less than 2 IJm and ran adjacent to the blood vessel wall, some fibers showed immunoreactivity to substance P. However, extremely thin nerve fibers closely intertwining with the blood vessel wall are not immunoreactive to substance P. The presence of perivascular substance P-immunoreactive nerve fibers may suggest the existence of

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inflammation and hyperalgesia caused by an axon reflex in the SAB. Neer 29 described a series of disorders caused by impingement of the humeral head on the anterior-inferior surface of the acromion and coracoacromial ligament with the elevation of the upper arm and called this disorder "subacromial impingement syndrome." He stated that inflammation of the subacromial bursa served as a primary step that can ultimately lead to rotator cuff tearing. Nociceptors such as free nerve endings, which are said to react to painful stimulation and inflammatory substances, were predominantly present at the side of the C-A arch, which is exposed to stress because of impingement between the humeral head and the C-A arch. We speculate such nociceptors receive nociceptive stimuli caused by the impingement and alert the body by making it perceptive of pain, thus preventing a disorder such as a rotator cuff tear. We thank Drs. Masami Yoshimoto and Naoyuki Yamamoto, Department of Anatomy, Nippon Medical School, for their invaluable assistance with this investigation. REFERENCES 1. Amara SG, Jonas V, Rosenfeld MG, Ong ES, Evans RM. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 1982;298:240-4. 2. Ashton IK, Roberts S, Jaffray DC, PolakJM, EisensteinSM. Neuropeptides in the human intervertebraldisc. J Orthop Res 1994;112:186-92 3 Birnbaum K, Lierse W. Anatomy and function of the bursa subacromialis. Acta Anat 19921145:354-63. 4. Canoso J]. Bursae, tendons and ligaments. Clin Rheum Dis 1981 ;7:189-221. 5. Chang MM, LeemanSE, Niall HD. Amino-acid sequence of substance E Nature (New Bid) 1971 ;232:86-7. 6. Codman EA. The shoulder. Boston: Thomas Todd, 1934. 7. Cuello AC. Synaptic organization of peptide-containing sensory neurons. Adv Pain Res Ther 1987; 10:1-8. 8. FerrellWR. The adequacy of stretch receptors in the cat knee ioint for signalling joint angle throughout a full range of movement. J Physiol 1980;299:85-99. 9. FreemanMAR, Wyke B. The innervationof the knee joint: an anatomical and histological study in the cat. J Anat 1967; 101:505-32. 10. Gardner E. The innervation of the shoulder joint. Anat Rec 1948;102:1-18. 11. Gibbins IL, Wattchow D, Coventry B. Two immunohistochemically identified populations of calcitonin gene-related peptide (CGRP)-immunoreactiveaxons in human skin. Brain Res 1987;414:143-8. 12. Grigg P, Hoffman AH. Propertiesof Ruffini afferents revealed by stress analysis of isolated sections of cat knee capsule. J Neurophysid 1982;47:41 54.

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28.

29. 30.

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