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									                                            Refered pain.
       Visceral and deep somatic pain are often referred, i. e., the pain is not felt in the dis-
eased structure itself, but at another place in the body far away from the sote of its origin
.Sometimes pain radiates from the diseased structure to the distant referral site.
       Pain is referred according to the dermotal rule, i. e., it is referred to the dermatome
(area of skin) supplied by the dorsal nerve roots through which impulses from the diseased
structure reach the CNS. But pain is projected to the area of skin in stead of the viscus or deep
somatic structure. Referred pain is therefore an error of projection.
       The sites to which pain from different structures may be referred can be deduced from
a knowledge of the segmental and peripheral innervatio n of the body.

                                   Mechanisms of referred pain.
       Convergence and facilitation both play a part in the production of referred pain.

                                        Convergence theory.
       According to this theory, pain fibres from an area of skin and a diseased viscus sup-
plied by the same spinal segment converge on the same second-order neurone in the dorsal
korn. The skin has a muchricher nerve supply than any viscus, and it is more exposed to
stimulation than any viscus. As a result, the somatosensory area of the ceebral cortex is more
used to receiving impulses from skin than from a viscus. Thus, the brain misinterprets im-
pulses coming along the common pathway as coming from the skin (i. e., the sensation is
projected to the skin area) and not from the viscus.

                                            Facilitation theory.
        Pain fibres from the skin ae always carrying impulses, but under normal conditions
 these are not enough to produce pain, i. e., the second-order neurones on which they converge
 are only subliminally stimulated (subthreshold stimulation ). When pain stimulated, they send
 impulses that converge on nearby second-order neurones (whichalso receive afferents from
 the skin ), thus increasing their excitability, i. e., facilitating them to reach the thres hold level
 of stimulation.
        As a result, minor stimuli in the pain pathway from the skin, which normally would
have died out in the spinal cord, pass on the brain.Since the brain is more used to receiving
impulses from the skin than from the viscera or deep somatic structure, the sensation is pro-
jected to the skin area. The result is pain felt in the area of skin and a lowering of its pain
threshold. The pain felt in the skin is referred pain, and the lowering of its pain threshold ac-
counts for the hyperalgesia and hyperaesthesia of the skin.
        Certain portions of the skin ae characterized by increased pain sesivity (Zakharyin-
Head zones ).

         Mascular rigidity and tenderness associated with visceral and deep somatic pain.
        The rigidity of nearly skeletal muscle associated with disease of a viscus is distributed
regionally andnot segmentally. and so its position varies acording topo the anatomical posi-
tion of the diseased viscus.
        The rigidity is most marced when the parietal peritoneum or pleura becomes irritated
by the diseased viscus.
       For example, the rigidity in the right idiac fossa that acco:~nanies acute appendicitis is
secondary to irritation of the patietal peritoneum by the inflamed appendix. However, rigidity
can occur without involment of the pleura or peritoneum.
       The spasm protects the underlying inplamed structure from tra uma. Indeed, this reflex
spasm is sometimes calledguarding. Yet, if it continues for long periods, the muscles become
ischemic and chemicals accumulate in them which reduce their pain thresholds. This account
for the soreness and tenderness of the rigid muscles.
        There is increasing evidence for a central enkephalinergic, mechanism for some kinds
 of itch. Naloxone suppresses the, itching in the trigeminal area which is commonly induced
 by, intrathecal opioids and it may suppress generalized itching, caused by liver disease or by
 butarphanol. With other, morphine- like analgesics itching may, however, be due to, release of
 histamine from mast cells in body tissues. Local, release of histamine is undoubtedly associ-
 ated with sensation, of itch.
        The reflex motor response (rhythmical scratching, automatism) is guite different from
 the withdrawal reflex, induced by pain. It is probably organized in the medulla in, association
 with the trigeminal sensory nucleus, at the upper, end of a spinotrigeminal chain of inter neu-
 rones from, enkephalin recepors in the substantia gelatinosa of the dorsal, horn of the spinal
 cord.
        It is also uncertain whether pricking, burning,cutting, and stabbing types of pain are
related but separate, sensations, or differ only in intensity and temporospaial, pattern of
stimulation. The dull aching pain aroused by, stimulation of viscera is thought by most
authorities to, differ from cutaneous pain and may be conveyed by a separate, system of nerve
fibres, mainly if not exclusively unmyelinated, as discussed above. The adeguate stimulus is
commonly, distension of a hollow viscus or blood vesses but it is, uncertain whether the re-
ceptors are mechanoreceptors, another, variety of chemoreceptor,or both. Even the aching
type of pain, in somatic tissues and especially migraine pain, tend to be, throbbing in nature.,
The relationship between pain and temperature sensations is also difficult to define.With in-
creasing heat stimulation,, the sensation of warmth passes insensibly to one of pain, and, wit h
increasing cold, a sensation of' paradoxical warmth' is, experienced before cold-pain. Nev-
ertheless, it is now accepted, that there are separate receptors for thermal sensations,, pro-
jecting to related parts of the diencephalon.
                                DISFUNCTION OF THE THYROID

       The disturbances in the functions of the thyroid are manifested mainly in disorders of
metabolism and the process-of growth and development. This has been demonstrated by the
results of extirpation of the thyroid in animals and the effects of thyroid extracts and hor-
mones on the processes of metabolism and metamorphosis in lower vertebrates.
       The discovery of thyroxin which is a parahydroxydiiodophenyl ether of diiodotyrosine
has greatly helped to study the problems connected with the pathology of this gland. Some
authors are inclined to ascribe the changes in the functions of the thyroid wholly to variations
in the content of thyroxin in the gland.
       Although the iodine-containing thyroxin and the extracts from the entire thyroid pro-
duce a very similar effect in the main functions of the organism (basal metabolism, growth,
heart action, etc.) the hormonal activity of the thyroid id not limited to production of thyroxin
alone. The dissimilar effects of thyroxin in different cases of thyroid insufficiency show that
the etiology of thyroid diseases cannot be explained only by increased or decreased produc-
tion of thyroxin. Thyroxin binds only part (20-25 per cent) of the total iodine of the thyroid.
The latter apparently also contains other iodine compounds which are likewise very active
physiologically. By hydrolysing iodothyroglobulin it is possible to obtain thyroxin and its an-
tagonist - diiodotyrosine; diiodothyronine, another organic iodine compound and second thy-
roid hormone, has been discovered in the blood by means of chromatography.

                   AFUNCTION AND HYPOFUNCTION OF THE THYROID

        Ablation of the thyroid in animals causes within a few weeks caxia thyreopriva which
 is characterised by diminished basal metabolism (an average of 12-35 per cent), decreased
 excretion of nitrogen in the urine and increased resistance of the organism to sugar.The tem-
 perature drops to the lowest normal level, there are trophic disorders of the skin and mucous
 membranes, the hair falls out, and the animals become apathetic, i.e., they keep lying about,
 can hardly move, become awkward and lose the formerly acquired conditioned reflexes.
        Removal of the thyroid in young growing animals arrests their growth and develop-
 ment. This condition is characterised by disturbances in ossificatio n of cartilages, failure of
 bones to grow in length, and persistence of epiphyseal sutures. Sexual development is clearly-
 retarded. The anterior lobe of the hypophysis and the adrenal cortex are enlarged.
        In cases of hypofunction or afunction of the thyroid human adults develop myxedema;
 the phenomena observed in man differ from those developing in experimental animals after
 removal of the gland.
        In this condition the skin is yellowish and has a waxy tint; it is pale, dry, tough and cold
to touch. The condition is characterised by swelling of the mucosa and noticeable deposition
of a mucinlike fluid in the subcutaneous cellular tissue of the face and certain other parts of
the body ( in region of the supraclavicular fossae, arms and legs). The swelling is not a result
of mucin formation, but is due to accumulation of protein-rich fluid in the tissues.
        Because of the swollen mucosa the face becomes dull and inexpressive; it od puffy and
its features are altered. A change in the voice (due to laryngeal diformity) and respiratory dif-
ficulties are observed. Respiration becomes shallow and slow. Tropic disorders appear - the
skin grows dry, the hair falls out, and the nails become brittle. The heart rate slows down, the
sexual function fails, and hypoplasia of tbe gonads is observed. Basal metabolism is noticeably
diminished (20-50 per cent). The specific dynamic effect of protein, nitrogen metabolism and
the heat exchange are decreased. Mild hypothyroidism may cause adiposis. Myxedema is
marked by generally diminished cerebration and obtusion of the reactive ability of the organ-
ism. These phenomena are based on weakened functions of the nervous system, especially the
cerebral cortex.
        The presence of hypothyroidism is also attested by the thyroid's lowered tolerance of
 the iodine isotope (I 131) administered into the organism.
        Childhood myxedema closely resembles the myxedema of adults, although it has cer-
 tain specific characteristics manifested in growth disorders (dwarfism) and disturbances in the
 development of the genitalia. The processes of cartilage ossification are impaires, and the
 zones of ossification between the diaphyses and epiphyses of tibular bones remain open.
 Enchondral and periosteal ossification is disturbed.
        All thess phenomena perceptibly diminish and some of them even disappear altogether
 as a result of ingestion of thyroid or injection of thyroid extract. These facts and the tempo-
 rary successful results produced by closely related forms of thyroid disease are actually hy-
 pothyroidism and athyroidism.
     ' Thyroid disease of a hypofunctional character is not infrequently accompanied by a
pathological enlargement of the thyroid, so-called goitre. However, enlargement of the gland
alone is not indicative of the character of affection which may be both hyper- and hypofunc-
tional, depending on the changes in the gland itself.
        Of the hypofunctional or afunctional states of the thyroid often accompanied by its en-
largement (goitre) mention must be made of so-called sporadic cretinism observed mainly in
children with congenital hypo- or athyroidism.
        m addition to sporadic, there is also endemic goitre. It is observed among inhabitants of
certain areas, especially in the mountains (Alps, Carpathians, Pamirs and Caucasus) and
highlands. Endemic goitre is sometimes accompanied by somatic underdevelopment and
rather marked mental retardation. The mucosa is either slightly swollen or not. The growth of
bones in length is delayed, ossification is retarded, the epiphyseal sutures close late. The
structure of the skeleton is impaired. Owing to the retarded development of the base of the
skull the nose remains sunken-in and flattened, the face is asymmetrical and puffy, the devel-
opment of the jaws and entire masticatory apparatus is defective. The skin is pale, dry and
wrinkled. The genitalia are underdeveloped. Basal metabolism is often normal. The amount
of iodine in the thyroid is diminished.
        The favourable results of prevention and treatment of emdemic goitre with iodine and
experimental production of changes in the thyroid analogous to endemic goitre attest that the
origin of this disease is connected with chronic deficiency of iodine in the water and food or
its improperutilisation by the gland. It is possibleto produce goitre in animals by depriving
them of iodine during fetal development or in the first months of life. In these casesthe thy-
roid is considerably enlarged. For example, in dogs given food deficient in iodine the weight
of the thyroid reaches 100 g within 18 months, whereas in the control animals given normal
food the gland weighs only 1 g.
        The possibility of producing goitre and reducing the function of the thyroid by means
of cyanides (for example, methyl cyanide, potassium thiocyanate) and thiocompounds (for
axample thiourea, thiouracil) has been established experimentally. The former depress utili-
sation of iodine by the thyroid, the latter - formation of hormones in the gland.

                            HYPERFUNCTION OF THE THYROID

        Exophthalmic goitre (Basedow's disease) and closely related thyrotoxicoses are hyper-
functional diseases of the thyroid.
        Exophthalmic goitre is characterised by an enlargement of the thyroid which is usually
caused by proliferation of the epithelium and its congestion, exophthalmos due to increased
tone of the smooth muscle situated behind the eyeball and having sympathetic innervation,
tachycardia produced by stimulation of the sympathetic nervous system of the heart, increased
metabolism (59 per cent and higher), excessive heat production and heat loss, and heightened
irrtability. This disease is caused by hyperfunction of the thyroid, which is evident a compari-
son of the symptoms of this disease with those of myxedema; the symptoms of the two dis-
eases are in many respects opposite to each other.
       That hyperthyroidism underlies exophthalmic goitre is also attested by the fact that the
thyroid retains radioactive iodine and that removal of part of the thyroid produces a favour-
able effect.
       Another proof is that a number of phenomena characteristic of this disease can be pro-
duced in animals by injection of thyroid extract and even thyroxin alone.
       The appearance of most of the aforementioned signs of exophthalmic goitre is due to
increased excitability of both the central and peripheral nervous systems, that of the sympa-
thetic division of the nervous system in particular. Every now and then, however, a form of
exophthalmic goitre with manifestations of increased activity of the parasympathetic division
of fhe nervous system is observed& Sometimes exophthalmic goitre develops suddenly, fol-
lowing a psychic trauna, which denotes dysfunction of the cerebral cortex in its pathogenesis.
In this cases the cerebral cartex exerts its influence on the function of the thyroid through the
subcortical region which is associated with the function of the anterior lobe of the hypophy-
sis.
       Some part in the mechanism of exophthalmic goitre may be playes by increased secre-
tion of a thyrotropic hormone by the hypophysis, a hormone which stimulates the function of
thyroid. The possibility that exophthalmic goitre may be directly stimulated by the central
nervous system is not excluded.
       The development of exophthalmic goitre also involves other endocrine glands; for ex-
ample, the functions of the pancreas and gonads are diminished. Involvement of other endo-
crine glands in the pathologic process in exophthalmic goitre perhaps explains why a thyroi-
dectomy sometimes proves ineffective.

                          DYSFUNCTION OF THE PARATHYROIDS

       Parathyroid insufficiency, especially total afunction of the parathyroids, leads to devel-
opment of tetany.
       Sluggishness, anorexia and thirst are observed in the animal (dog or monkey) already
on the second day after complete removal of the parathyroid glands. 48-72 hours after the op-
eration in cases of acute development of the symptoms the animal exhibis signs of increased
neuromuscular excitability - motor disorders manifested in quiverings of the muscles and un-
steady gait; the limbs seem to become stiff and unable to bend; the disorder is characterised
by tonic spasms of the limbs. Intermittent clonic spasms are observed soon afterwards.
       The foregoing phenomena are followed by an acute attack of tetany with manifesta-
tions of excitation of the cenral nervous system in the form of tonic spasms, laryngospasm,
vomiting and severe diarrhea. The intensity of the these phenomena differs in different ani-
mals. In cases of severe dyspnea and tachycardia the very first attack may lead to death, but
more often the animal survives; then comes the second attack, sometimes the third, etc. Dur-
ing one of the attacks the animal dies as a result of spasm of the respiratory muscles, the dia-
phragm and the rima glottidis.
       In cases of chronictetany these symptoms are mild and tropic disorders come to the
fore - emaciation, loss of hair, purulent affection of the eyes, development of cataracts, ir-
regular ossification and calcification of the teeth and destraction of the enamel which lead to
dental fractures with ulcers forming on the mucosa nea the sites of the fractures.
       A meat diet hastens the onset of attacks since in this case various protein metabolites
accumulate in the organism more rapidly, guanidine bases particulary hastening the onset of
attacks of tetany.
       In man tetany is most commonly observed in childhood. The symptoms of this disease
are not so clearly pronounced as in experimental tetany. Tetany may also occur in adults as a
                                                                                                      /

quent deformations and fractures of bones. These cases are marked by increased calcium, di-
minished phosphorus and increased excreti
      This disease often exhibits adenomatous proliferation of the parathyroid flands. By re-
peated injections of aclive,parathyroid preparations it has been possible to produce bony
changes in dogs similar to those found in patients with generalised fibrous osteodystrophy.

                              DYSFUNCTION OF THE HYPOPHYSIS

        The studies of the dysfunction of the hypophysis cerebri and its effects on the ofganism
go considerably beyond this gland because the nuclei of the diencephalon (nucleus supraopti-
cus and nucleus paraventricularis) are connected by nerve fibres with the posterior lobe of the
hypophysis and form with it a single diencephalohypophyseal system. Impairment of this
system underlies a number of diseases. The same pathologic phenomena may be experimen-
tally produced by stimulating the posterior lobe of the hypophysis and the diencephalon.
        Information is now available concerning neurosecretion by the nuclei of the anterior
portion of the hypothalamus and the influence of the hormones they secrete on the function of
the adenohypophysis (Bergmann).
        The connections between the cerebral cortex and the internal organs are maintained not
only throughthe inferior parts of the nervous system, but also through the hypophysis. Dys-
function of the cerebral cortex may therefore cause disterbances in a number of visceral
functions also neurohypophyseally.
       The hypophysis secretes about 25 hormones some of which regulate the basic functions
of the organism. All of these hormones are apparently of an albuminous nature.

                  EXPERIMENTAL DYSFUNCTION OF THE HYPOPHYSIS

        Ablation of the anterior lobe of the hypophysis in young animals causes mainly an ar-
 rest of growth and sexual development. On the other hand, administration of extracts from the
 anterior lobe of the hypophysis results in increased growth of animals.
        The delayed growth of the tubular bones in cases of hypofunction of the anterior lobe
of the hypophysis in manifested in retarded closure of the epiphyseal suture. It is also marked
by long persistence of the milk teeth, metabolic disterbances (increased limit of sugar as-
similation, and phenomena of adiposis), drop in body temperature and impaired heat regula-
tion. Atrophic changes are also observed in other endocrine glands, mainly in the adrenal
cortex, the pancreas and thyroid. The animals remain infantile; the development of the gonads
is retarded and the glands are smaller in size; the external genitalia are also poorly developed.
        The participation of the anterior lobe of the hypophysis in the processes of growth and
development is expressed in its secretion of a somatropic hormone which stimulates the
growth of young animals.
        Of the other phenomena observed after removal of the anterior lobe of the hypophysis
mention must be made of adiposis and hypofunction of the gonads.
        Afunction of the crinogenic hormones of the anterior lobe of the hypophysis caused
dysfunction of the corresponding endocrine glands. Afunction of the thyrotropic hormone
leads to hypofunction of the animal's thyroid, while afunction of the adrenocorticotropic hor-
mone (ACTH) results in hypofunction of the adrenal cortex which leads to diminished basal
metabolism, adynamia and extinction of the function of the gonds.
        Particulary noticeable is the effect of afunction of the anterior lobe of the hypophysis or
its extract on the function of the gonads and through them on the entire system of reproduc-
tive organs and secondary sex characters. This effect is conditioned by the gonadotropic hor-
mones of the anterior lobe of the hypophysis.
        Removal of the posterior lobe of the hypophysis usually causes polyuria which soon
passes, although in some cases it persists for a long time. The antidiuretic hormone produced
by the posterior lobe of the hypophysis perceptibly reduces the excretion of urine, especially
in cases of polyuria, by stimulating reabsorption of water in the renal tubules. Very brief
polyuria is observed in cases of total removal of the hypophysis. For the onset of prolonged
polyuria it is necessary to preserve the anterior lobe of the gland. It is therefore believed that
polyuria developing after removal of the posterior lobe of the hypophysis is due to an increase
in the diuretic function of the anterior lobe of the fland. An extract from the posterior lobe of
the hypophysis, whych inhibits the excretion of urine, constricts the arterioles and capillaries,
thereby elevating the arterial pressure, and causes a slowing of the heart rate. The antidiuretic
and vasoconstrictor effect is due to the action of vasopressin, the hormone of the posterior
lobe of the hypophysis. This hormone is a peptide containing nine residues of amino acids
and twelwe-member cycle formed by disulfide bridges.
    • Oxytocin, another hormon, which very closely resembles vasopression in chemical
structure, has also been isolated fromtho posterior lobe of the hypophysis. Both these hor-
mons have now been produced synthetically.
       Oxytocin raises the tone of the uterus, the smooth muscles of the intestines, the bladder
and gallbladder. Extracts from the posterior lobe have long been used to stimulate labour. The
uterusof a sexually immature guinea pig is particulary sensitive to extracts from the posterior
lobe of the hypophysis.
       The hormones of the posterior lobe of the hypophysis are formed in the neurosecretory
cells of the supraoptic and paraventricular nuclei of the hypothalamus whence they pass into
the posterior lobe of the gland. They are secreted under the regulatory influence of the nerv-
ous system.
       Intermedin, a melanocyte-stimulating hormone which alters, in particular, the size of
the melanophores (pigment cells) in the skin of frogs, has been isolated from the intermediate
lobe of the hypophysis.

    HYPOFISNCTION OF THE ANTERIOR LOBE OF THE HYPOPHYSIS IN MAN

        Hypophyseal infantilism in man is the result of hypofunction of the anterior lobe of the
 hypophysis, insufficient secretion of the somatotropic hormone.
        Early destruction (for example, by a tumour) of the anterior lobe of the hypophysis may
 lead to dwarfism with normal bodily proportions and mental development generally corre-
 sponding to age, with underdeveloped genitalia and senile appearance.
       Hypofunction of the hypophysis often causes adiposogenital dystrophy. This disease is
characterised by deposition of fatty substances in the subcutaneous adipose layer, especially
of the chest, abdomen and pelvis, and is accompanied by underdevelopment of the gonads
and the secondary sex characters. The skin is thick, dry, cold and somewhat edematous. In
young, growing individuals the disease is manifested not only in adiposis, but also in arrested
growth, persistence of the epiphyseal suture of the tubular bones, and underdevelopment of
the gonads and the secondary sex characters.
       But such adiposis may also develop with a seemingly intact hypophysis in cases of hy-
drocephaly or a tumour growing at some distance from the gland. These cases apparently in-
volve dysfunction of the central vegetative zones of the diencephalon (the infundibulum and
floor of the third ventricle) and impairment of their connections with the hypophysis.
       Acute hypophyseal hypofunction in man leads to development of a severe disease - hy-
pophyseal cachexia or Simmond's disease. This disease is characterised by extreme emacia-
tion, diminished metabolism, atrophy of the bones, loss of hair and teeth, atrophy of the sex-
ual apparatus, the thyroid and adrenal cortex. Many of these phenomena are the opposite of
those observed in acromegaly which is caused by hyperfunction of the anterior lobe of the
hypophysis. Afunction of the hypophysis, which is responsible for hypophyseal cachexia. is
due to embolism of the hypophyseal vessels or destruction of the hypophysis by tuberculosis,
syphilis or tumours.
       Phenomena resembling those of hypophyseal cachexia in man may be observed in ex-
periment (in rats) after removal of the hypophysis.
       Lastly, diabetes insipidus is also caused by dysfunction of the posterior lobe of the hy-
pophysis. It also develops in cases of tumours and infectious processes on the base of the
brain as a result of impairment of the diencephalon and its connection with the posterior lobe
of the hypophysis.

   HYPERFUNCTION OF THE ANTERIOR LOBE OF THE HYPOPHYSIS IN MAN

        Acromegaly is due ti hyperfunction of the anterior lobe of the hypophysis, and exces-
sive secretion of the growth hormone. It most commonly occurs in cases of neoplastic prolif-
eration of the anterior lobe (adenoma) This disease manifests itself in a fullgrown organism in
excessive growth of the fingers and toes, supraorbital ridges, nose, chin and cheekbines; the
hands and feet are considerably enlarged. The growth affects mainly the bones and soft tis-
sues.
       Owing to secondary lesions in the sella turcia acromegaly is accompanied by impair-
ment of vision, dizziness, vomiting and headache. Moreover, the onset of the disease is char-
acterised by increased sexual desire which subsequently descreases. Disturbances are ob-
served in protein, carbohydrate and salt metabolism (for example, glycosuria).
       If hyperfunction of the anterior lobe of the hypophysis occurs in a growing organism,
its results is hypophyseal gigantism which is characterised by excessive bodily growth with
normal proportions. The epiphyses of the tubular bones long remain open. Proliferation of the
basophilic cells of the anterior lobe of the hypophysis (basophilic adenoma) underlies Cush-
ing's disease (pituitary basophilism) which is characterised by adiposis o f the face, neck and
trunk ( but not the limbs), elevated blood pressure and an increased erythrocyte count, hypo-
genitalism (phenomena of masculinisation in women), hyperglycemia and glycosuria. In this
disease the adrenal cortex is usually also hypertrop hied.

          CONNECTIONS OF THE HYPOPHYSIS WITH THE OTHER GLANDS

        Studies of the disorders of the hypophyseal function have made it possible to establish
 connections of the anterior lobe of the hypophysis with the thyroid, adrenal cortex, gonads
 and pancreas.
        Extracts of the anterior lobe of the hypophysis contain a thyrotropic hormone which
causes hyperplasia and stimulates the function of the thyroid. Hyperfun
								
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