Flemming W. Bach

Histamine- and Stress-Induced Secretion of ACTH and β-Endorphin: Involvement of Corticotropin-Releasing Hormone and Vasopressin

Histamine (HA) stimulates the release of the pro-opiomelanocortin (POMC)-derived peptides ACTH, beta-endorphin (beta-END), beta-lipotropin and alpha-melanocyte-stimulating hormone, and HA is involved in the mediation of the stress-induced release of these peptides. The effect of HA is indirect and may involve the hypothalamic regulating factors, corticotropin-releasing hormone (CRH) and/or arginine-vasopressin (AVP). We studied the effect of immunoneutralization with specific antisera against CRH or AVP on the response of ACTH and beta-END to HA, restraint stress, CRH, AVP or a posterior pituitary extract in male rats. Intracerebroventricular infusion of HA (34-540 nmol) increased the plasma levels of ACTH and beta-END immunoreactivity (beta-ENDir) in a dose-dependent manner. Pretreatment with antiserum to CRH or AVP prevented the ACTH response to 270 nmol HA and inhibited the beta-ENDir response by 30-60%. One to five minutes of restraint stress caused an increase in the plasma levels of ACTH and beta-ENDir. The increase was dependent on the duration of stress exposure. Pretreatment with CRH antiserum abolished the ACTH response to 5 min of restraint stress and inhibited the beta-ENDir response by 60%. Immunoneutralization with AVP antiserum had only half the inhibitory effect of that seen with CRH antiserum. CRH (100 pmol i.v.) increased the plasma levels of ACTH and beta-ENDir. This effect was abolished by pretreatment with CRH antiserum, whereas pretreatment with AVP antiserum prevented the CRH-induced ACTH release and inhibited the beta-ENDir response by 50%. AVP (24-800 pmol i.v.) stimulated ACTH and beta-ENDir in a dose-dependent manner. CRH and AVP antisera each prevented the effect of AVP (800 pmol) on ACTH secretion, whereas the beta-ENDir response to AVP was only inhibited by about 60% by the antisera. An extract of the posterior pituitary gland administered in a dose corresponding to 0.15 or 0.5 pituitary equivalents had no effect on ACTH secretion, while 1.0 pituitary equivalent increased the ACTH concentration in plasma. This effect was abolished by AVP antiserum. The posterior pituitary extract caused a dose-dependent rise in plasma beta-ENDir which might be due to an unavoidable contamination of the posterior pituitary extract by a small amount of beta-END from the intermediate lobe. Consistent with this view, AVP antiserum had no effect on the rise in the plasma concentration of beta-ENDir following administration of the posterior pituitary extract.(ABSTRACT TRUNCATED AT 400 WORDS)

Increased cerebrospinal fluid Met-enkephalin immunoreactivity in patients with chronic tension-type headache

&NA; Cerebrospinal fluid (CSF) concentration of Met‐enkephalin immunoreactivity (Met‐enkephalin‐ir) was determined by radioimmunoassay in 47 patients with chronic tension‐type headache and in 47 headache‐free control subjects. Thirty‐nine of the controls were patients receiving spinal analgesia before surgery for diseases not associated with pain; 8 were healthy paid volunteers. Patients reporting migraine more than 1 day per month were excluded. Pericranial tenderness, nociceptive flexion reflex and thermal pain thresholds were determined in the majority of the patients. The median level of CSF Met‐enkephalin‐ir was significantly higher (115 pmol/1) (quartiles (107–134) pmol/1) in the headache patients than in the controls (median 79 pmol/1) (quartiles (73–87) pmol/1) (Mann‐Whitney, P < 0.001). No indication of sex‐difference or correlation with age with respect to CSF Met‐enkephalin‐ir was found. No correlation was found between CSF Met‐enkephalin‐ir and either pericranial tenderness, nociceptive flexion‐reflex threshold, or thermal pain threshold. There was no indication of correlation between consumption of mild analgesics and CSF Met‐enkephalin‐ir. The higher levels of CSF Met‐enkephalin‐ir in the headache patients may be indicate activation of the enkephalinergic antinociceptive system at the spinal/ trigeminal level, whereas the &bgr;‐endorphinergic system appears normal. This enkephalinergic activation may be caused by increased activity in the primary nociceptive afferents, or may be compensatory to decreased activity in other endogenous antinociceptive systems than the opioid.

Plasma and cerebrospinal fluid β-endorphin in chronic tension-type headache

&NA; Previous studies have provided evidence of an increased sensitivity to pain, a decreased hypothalamic opioid tone, and decreased cerebrospinal fluid (CSF) &bgr;‐endorphin (&bgr;‐EP) concentration in patients with primary chronic headache. We applied separate specific radioimmunoassays for &bgr;‐EP in CSF and plasma on samples from age‐matched controls and a group of 50 patients with chronic tension‐type headache (CTH) fulfilling the diagnostic criteria set by the International Headache Society. Median CSF &bgr;‐EP concentrations (95% confidence limits) were 12.8 pmol/1 (11.0–14.5) in CTH patients and 11.9 pmol/1 (10.9–14.2) in the control group, which is not significantly different (P = 0.28). Plasma &bgr;‐EP concentrations did not differ either, being 3.1 pmol/1 (2.4–3.7) and 3.3 pmol/1 (1.8–4.0) in the patients with CTH and in controls, respectively (P = 0.88). Plasma and CSF &bgr;‐EP concentrations did not correlate. Reversed‐phase high performance liquid chromatography (HPLC) of CSF pools from the headache patients and controls revealed similar profiles of &bgr;‐EP‐immunoreactivity both when C‐terminally and N‐terminally directed antisera were used, suggesting a normal post‐translational processing of the pro‐opiomelanocortin gene in patients with CTH. &bgr;‐EP is not involved in the pathogenesis of CTH, or such a role is not reflected in CSF or plasma concentrations of the neuropeptide.

Impaired Histamine- and Stress-Induced Secretion of ACTH and β-Endorphin in Vasopressin- Deficient Brattleboro Rats

Arginine vasopressin (AVP), corticotropin-releasing hormone (CRH) and catecholamines seem to be involved in the histamine- (HA) and/or stress-induced release of the pro-opiomelanocortin-derived peptides adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END). The AVP component of the regulatory mechanism can be specifically studied in Brattleboro rats which lack AVP. These animals may therefore serve as a useful biological model for investigating the importance of AVP in the ACTH and beta-END response to HA and stress. On this background, we studied the ACTH and beta-END response to HA or restraint stress in conscious, male dizygotic AVP-deficient Brattleboro rats (DI) and compared the hypothalamic content of CRH and catecholamines in these rats with that of nondiabetic isogenic Long-Evans rats (LE). In addition, we studied the hypothalamic AVP content in LE rats after HA infusion or exposure to restraint stress. HA (270 nmol) administered intracerebroventricularly (i.c.v.) or 5 min of restraint stress caused a 6- to 7-fold increase in plasma concentrations of ACTH and beta-END in LE rats but only a 2- to 3-fold increase in DI rats (p < 0.01 vs. LE). The basal hypothalamic content of CRH and catecholamines (epinephrine, norepinephrine, and dopamine) was similar in DI and LE rats. The hypothalamic AVP content in LE rats was unaffected by central HA infusion or restraint stress and was undetectable in DI rats. We conclude that inherited lack of AVP impaired the ACTH and beta-END response to central HA administration as well as to restraint stress, suggesting that AVP is important for the mediation of these responses.

Responses of Anterior Pituitary Hormones and Hypothalamic Histamine to Blockade of Histamine Synthesis and to Selective Activation or Inactivation of Presynaptic Histamine H3 Receptors in Stressed Rats

The stress-induced release of anterior pituitary hormones and changes in hypothalamic content of histamine (HA) and its metabolite tele-methylHA (t-meHA) were studied in male rats during inhibition of HA synthesis or activation or blockade of HA H3 receptors. Pretreatment with the HA synthesis inhibitor alpha-fluoromethylhistidine (alpha-FMH; 200 micrograms intracerebroventricularly (icv) at -120 min) or the specific H3 receptor agonist R(alpha)methylhistamine (RmHA; 10 mg/kg intraperitoneally (ip) at -180 and -60 min) inhibited by 30-80% the responses of prolactin (PRL), corticotropin (ACTH) and beta-endorphin (beta-END) immunoreactivity to 1, 2.5 or 5 min of restraint stress (p < 0.05-0.01), but had no effect on basal secretion of the hormones. The inhibitory effect of the H3 receptor agonist RmHA (10 mg/kg x 2) on the hormone response to 5 min of restraint stress was prevented by simultaneous ip administration of the H3 receptor antagonist thioperamide. alpha-FMH reduced the hypothalamic content of HA 60% and that of t-meHA 30%, while RmHA had no effect on the HA content. Restraint stress for 5 min did not affect the HA and t-meHA contents, which may be due to the short duration of stress exposure. Pretreatment with the H3 receptor antagonist thioperamide (5 or 10 mg/kg ip at -120 min) had no effect on basal or restraint stress-induced release of PRL, ACTH or beta-END, although the compound increased the hypothalamic content of t-meHA 2-fold.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress-Induced Secretion of Pro-Opiomelanocortin-Derived Peptides in Rats: Relative Importance of the Anterior and Intermediate Pituitary Lobes

Stress stimulates secretion of the pro-opiomelanocortin (POMC)-derived peptides adrenocorticotropic hormone (ACTH), beta-endorphin (beta-END) and alpha-melanocyte-stimulating hormone (alpha-MSH) from the anterior lobe (AL) and intermediate lobe (IL) of the pituitary gland. The secretion of POMC-derived peptides from the AL and IL is differentially regulated and the relative contribution of the lobes may vary with the stimulus. We investigated (1) the relative importance of the AL and IL as source of POMC-derived peptides released in response to restraint and ether stress by selectively inhibiting the corticotropes of the AL by dexamethasone (DEX) or selectively inhibiting the melanotropes of the IL by bromocriptine (BR), and (2) whether beta-adrenergic blockade by propranolol could be used to discriminate between the stress-induced effect on POMC secretion from the AL and IL as has previously been suggested. Selective inhibition of AL secretion by DEX totally blocked the ACTH response to restraint and ether stress, but only partially inhibited the beta-END response. The alpha-MSH response to both stressors was not affected by DEX. Conversely, selective inhibition of IL secretion by BR totally blocked the alpha-MSH response to both stressors, partially inhibited the beta-END response but did not influence the ACTH response. In response to restraint stress, beta-END was secreted equally from the AL and IL, whereas the IL was the most important source of beta-END in response to ether stress. Blockade of beta-adrenergic receptors with propranolol inhibited the beta-END- and alpha-MSH responses to restraint stress whereas the ACTH response was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Histamine H1 and H2 Receptor Activation Stimulates ACTH and β-Endorphin Secretion by Increasing Corticotropin-Releasing Hormone in the Hypophyseal Portal Blood

Histamine (HA) stimulates the release of adrenocorticotropic hormone (ACTH) and beta-endorphin (beta-END) via activation of central postsynaptic H1 or H2 receptors. The effect of HA is indirect and may involve the hypothalamic regulating factors corticotropin-releasing hormone (CRH), arginine vasopressin, or oxytocin (OT). We studied the effect of specific HA H1 or H2 receptor agonists on the concentration of CRH and OT in hypophyseal portal blood in urethane-anesthetized male rats. In addition we investigated the effect of the agonists on ACTH and beta-END immunoreactivity in peripheral plasma in conscious male rats pretreated with antiserum to CRH. Intracerebroventricular administration of the H1 receptor agonist 2-thiazolylethylamine (2-TEA) or the H2 receptor agonist 4-methylhistamine (4-MeHA) increased the CRH concentration in pituitary portal blood by 80-90% when compared to preinfusion levels (p < 0.05). Central infusion of saline had no effect. The level of OT in the pituitary portal blood was not affected by 2-TEA or 4-MeHA when compared to saline-treated rats. Intracerebroventricular infusion of 2-TEA or 4-MeHA increased the ACTH concentration in peripheral plasma 3- or 4-fold, respectively (p < 0.01). Pretreatment with a specific CRH antiserum (abCRH) inhibited the responses by 50 and 70%, respectively (p < 0.01). Intracerebroventricular administration of 2-TEA or 4-MeHA increased the beta-END immunoreactivity in peripheral plasma 3- or 2-fold, respectively (p < 0.01). These effects were inhibited by 80-90%, when rats were pretreated with abCRH (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Frequency, diagnosis, and prognosis of spinal cord compression in small cell bronchogenic carcinoma. A review of 817 consecutive patients

A retrospective review of 817 consecutive patients with small cell bronchogenic carcinoma disclosed 29 cases of spinal cord compression (frequency, 3.5%). Twelve patients (group 1) presented with symptom of cord compression, whereas the remaining 17 patients (group 2) developed this complication during therapy. Clinical features differed in the two groups: pain was present in 83% of the patients in group 1 and in 47% of those in group 2. Pain preceded motor dysfunction in 75% and 12% of the two groups, respectively. Radiologic bone destruction of the spine was found in 11 of 12 patients in group 1 and in 3 of 16 patients in group 2. Myelography was performed in 8 patients in group 1 and in 14 patients from group 2. A complete block was found in seven and none of the patients in each of the two groups, respectively. Treatment with irradiation and/or laminectomy rarely resulted in a significant improvement of preexisting neurologic impairment but it frequently prevented the progression of symptoms, leading to preservation of sphincter control and ambulatory function in eight of nine and seven of eight patients, respectively. Careful evaluation is mandatory for patients presenting with back pain and radiographic evidence of bone destruction, as 11 of 26 such patients were found to have spinal cord compression. It is concluded that spinal cord compression presents in two distinct ways. One with early onset, pain, evidence of bone destruction, and complete myelographic block. The second is characterized by motor impairment with no evidence of bone destruction and only partial myelographic block. Treatment rarely ameliorates symptoms but prevents deterioration, making early diagnosis important.

Plasma β-endorphin during clinical and experimental ischaemic pain

An improved radio-immunoassay using an antiserum directed towards the N-terminal part of the endogenous opioid peptide β-endorphin 1–31 (β-EP) was validated and applied to a study of β-EP in plasma during ischaemic pain. Experimental ischaemic pain induced in seven healthy volunteers by the submaximal effort tourniquet test did not change plasma β-EP or adrenocorticotrophin. Plasma β-EP was determined in 21 patients with acute myocardial infarction (AMI) and in seven patients with unstable angina pectoris. Plasma β-EP was 4.9 fmol/ml with 95% confidence limits, 3.2–7.8 fmol/ml in AMI patients at admittance, and 2.9 (2.0–3.4) fmol/ml one week later in stable and pain-free condition (p<0.05). The level in 49 healthy persons was 2.8 (2.4–2.9) fmol/ml. Elevated β-EP levels were found in five AMI patients with cardiogenic shock and in four AMI patients dying within 24 h after admittance compared to the rest of AMI patients (p<0.02). β-EP was not elevated during unstable angina pectoris, although pain scores we...

Cytostatic extravasation. A serious complication of long-term venous access

Totally implantable ports have gained popularity as venous access in the treatment of cancer. A case is reported with an uncommon but very serious complication, i.e., cytostatic extravasation secondary to a broken implanted catheter. Guidelines for implantation and remedies are recommended.