Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

In 30 patients with diagnosed fibromyalgia, the CSF level of immunoreactive substance P (SP) was investigated. Compared to normal values (9.6 +/- 3.2 fmol/ml), all the patients had elevated CSF levels of SP (36.1 +/- 2.7 fmol/ml, range 16.5-79.1 fmol/ml). Anamnestic information from the patients revealed that 53.3% had Raynaud/Raynaud-like phenomenon localized in the fingers, the toes or both. Although SP levels did not differ significantly in patients with or without the Raynaud phenomenon, elevated activity may be present in the peripheral branches of SP neurons which could be responsible for the last (rubor) phase of the triphasic Raynaud's phenomenon. SP levels were significantly higher in patients who were smokers (40.1 +/- 2.7 fmol/ml, range 25.3-64.1 fmol/ml), compared to patients who were non-smokers (29.2 +/- 5.0 fmol/ml, range 16.5-79.1 fmol/ml). We propose elevated CSF levels of SP and the Raynaud phenomenon as characteristic features for fibromyalgia with potential as diagnostic markers of the disease and further that smoking might be an aggravating factor for its pathogenesis or development.

Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis.

The cerebral circulation is invested by a rich network of neuropeptide Y (NPY) and noradrenaline containing sympathetic nerve fibers in arteries, arterioles and veins. However, the nerve supply of vasoactive intestinal peptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) containing fibers is sparse. While noradrenaline and NPY cause vasoconstriction, VIP, SP and CGRP are potent vasodilators. Stimulation of the trigeminal ganglion in cat and man elicits release of SP and CGRP. Subjects with spontaneous attacks of migraine show release of CGRP in parallel with headache. Cluster headache patients have release of CGRP and VIP during bouts. Treatment with sumatriptan aborts headache in migraine and cluster headache as well as the concomitant peptide release.

Neuropeptides in Migraine and Cluster Headache

The liver plays a key role for the maintenance of blood glucose homeostasis under widely changing physiological conditions. In the overnight fasted state, breakdown of hepatic glycogen and synthesis of glucose from lactate, amino acids, glycerol, and pyruvate contribute about equally to hepatic glucose production. Postprandial glucose uptake by the liver is determined by the size of the glucose load reaching the liver, the rise in insulin concentration, and the route of glucose delivery. Hepatic glycogen stores are depleted within 36 to 48 hours of fasting, but gluconeogenesis continues to provide glucose for tissues with an obligatory glucose requirement. Glucose output from the liver increases during exercise; during short-term intensive exertion, hepatic glycogenolysis is the primary source of extra glucose for skeletal muscle, and during prolonged exercise, hepatic gluconeogenesis becomes gradually more important in keeping with falling insulin and rising glucagon levels. Type 1 diabetes is accompanied by diminished hepatic glycogen stores, augmented gluconeogenesis, and increased basal hepatic glucose production in proportion to the severity of the diabetic state. The hyperglycemia of type 2 diabetes is in part caused by an overproduction of glucose from the liver that is secondary to accelerated gluconeogenesis.

Splanchnic Regulation of Glucose Production

Somatostatin (Sms) and its agonist analogues inhibit the secretory activities of endocrine and neural cells. Recent studies have suggested that Sms has significant immunomodulatory properties. In this study, we examine the effects of two Sms octapeptide analogues on the inflammatory reaction in vivo. BIM 23014 (Somatulin) and Sandostatin were administered to male Sprague-Dawley rats subject to carrageenin-induced aseptic inflammation, at doses of 2-10 micrograms/rat, given either systemically or locally. Animals were killed 7 h after the induction of the inflammation, and the inflammatory exudates were aspirated and quantitated in terms of volume and leukocyte concentration. Sms analogues, administered via either route, significantly reduced the volume and the leukocyte concentration of the exudate in a time- and dose-dependent fashion. In corroboration of these, immunohistochemical evaluation of the levels of local inflammatory mediators, such as immunoreactive (Ir) TNF-alpha, Irsubstance P, and Ircorticotropin-releasing hormone, was inhibited significantly by Sms analogue treatment. These findings suggest that Sms analogues have significant antiinflammatory effects in vivo, associated with suppression of proinflammatory cytokines and neuropeptides. Furthermore, these data suggest that Sms agonists may be useful in the control of inflammatory reaction.

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Somatostatin analogues suppress the inflammatory reaction in vivo.

Substance P (SP), present in sensory afferent neurons, seems to process nociceptive information in the trigeminal system. SP, released from peripheral trigeminal endings, causes typical cluster headache (CH) signs, e.g. vasodilatation, conjunctival and nasal edema and miosis. Opiates and somatostatin (SRIF), both active in relieving CH attack, inhibit SP release from the central and peripheral trigeminal system. In the present study, plasma and cerebrospinal fluid (CSF), SP-like immunoreactivity (SPLI) and enkephalinase activity (EKA), and plasma SRIF-like immunoreactivity (SRIFLI) have been evaluated during spontaneous and histamine induced attacks in the cluster phase. During the histamine provoked attacks, CSF SPLI and plasma SRIFLI and EKA were unchanged, while plasma SPLI decreased significantly. During spontaneously occurring attacks, plasma SRIFLI was found to be unmodified and a significant lowering of SPLI was detected when compared with controls. Moreover, both during and between attacks in the cluster phase, plasma EKA was increased in comparison with the values in controls. It remains to be seen whether variations of plasma SPLI and EKA levels play a role in the CH mechanism.

Substance P mechanism in cluster headache: evaluation in plasma and cerebrospinal fluid.

Vasodilatation, conjunctival and nasal edema as well as miosis are symptoms associated with cluster headache (CH) attacks. Similar symptomatology is caused by substance P (SP) release from peripheral trigeminal nerve endings. The symptomatic effect of somatostatin (SRIF) during CH attacks was attributed to the inhibition of SP release from trigeminal neurons. This study was designed to evaluate both the vascular effect of SRIF on the dorsal hand vein and SRIF plasma levels prior to and after subcutaneous and intranasal administration in CH patients. A powerful venoconstriction and tachyphylaxis were demonstrated when SRIF was administered both as bolus and infusion. Plasma levels of SRIF in CH sufferers were lower than in control subjects. Subcutaneous and intranasal SRIF administrations induced maximal plasma levels after 5 and 10 min, respectively. These data suggest that SRIF plays an important role during CH attacks; however, its exact mechanism of action is still to be defined.

A pharmacological approach to the analgesizing mechanism of somatostatin in cluster headache.

Cluster headache (CH) is a hemicraniofacial painful syndrome characterized by ip-silateral miosis and various vasomotor phenomena such as vasodilatation, salivation, nasal secretion, lacrimation and conjunctival congestion. A subpopulation of primary afferent neurons, projecting to the substantia gelatinosa in the spinal cord and to the corresponding area in the nucleus caudalis of the trigeminal nerve was shown to contain somatostatin (SRIF) and substance P (SP). The role of SRIF remains unclear, while that of SP is in the mediation of the antidromic vasodilatation. SP also appears to be the transmitter of pain signals [9]. Opiates and SRIF were capable of blocking the release of SP from both peripheral [2, 11] and central [13] nerve endings. SP induces miosis, edema of the nasal mucosa, vasodilatation. This striking similarity between SP function, trigeminal “topography,” and CH symptoms leads us to try SRIF as a symptomatic therapeutic agent in CH attack.

Somatostatin for Cluster Headache Attack

The role of liver in glucose homeostasis in type 2 diabetes: The modernity of claude bernard's studies

Migraine (M) shows increased\"susceptibi1ity\"to some drugs mainly concerning apparatuses, vegetative and nociceptive, involved in M attacks. So thel'headache susceptibilityl'to pain producing agents (histamine, bradykinin), the \"vomiting susceptibility\" to dopaminomimetic drugs (apmorphine, lisuride) , the\"co1lapsory susceptibility\", of dramatic extent in syncopal migraine to drugs (as bromocriptine) which inhibit the release of noradrena1ine.These evidences have suggested the hypothesis that the veqeto-nociceptive syndromes, grouped on the epOnymnMn,are the expression of an impaired neuronal secretion of transmitter with consequent hyperreactivity of the effector cell. The concept of \"functional denervation\" has been recently extended from the vegetative (efferent) nerves (deefferentation) to the nociceptive (afferent) apparatus (deafferentation). At this step of theorization,three main questions arise: a) if this putative denervation condition is cornpensatory,that is if it depends on a poor secretion of interested neurons with consequent supersensitivity ; b) if this condition is secondary, that is if denervation is adaptative (or compensatory) to a primary amplified intrinsic energy of the cell; c) if the anomalous condition of neuroeffector function is selectively circumscribed to the M-involved functions or if it is ubiquitarious. The rationale of the present investigation is an approach to the question of this last point: if a drug,which does not provoke any clinical reaction in M sufferers,is capable of activating cells of structures not M-involved , in a major extent in M sufferers than in normals,this could vaguely support the hypothesis that migraine perhaps is not a local but rather a systemic disorder. Glucagon (G) and cyclic AMP ( CAMP) seem to be respectively the suitable stimulus and the plasma parameter for this question. In

Daniela Caleri

Papers

Substance P mechanism in cluster headache: evaluation in plasma and cerebrospinal fluid.

A pharmacological approach to the analgesizing mechanism of somatostatin in cluster headache.

Somatostatin for Cluster Headache Attack

The role of liver in glucose homeostasis in type 2 diabetes: The modernity of claude bernard's studies

Effects of glucagon on plasma cyclic AMP in headache sufferers.