Is there a rational basis for cannabinoids research and development in ocular pain therapy? A systematic review of preclinical evidence.

BACKGROUND: Purpose of the present systematic review is to investigate preclinical evidence in favor of the working hypothesis of efficacy of cannabinoids in ocular pain treatment. METHODS: Literature search includes the most relevant repositories for medical scientific literature from inception until November, 24 2021. Data collection and selection of retrieved records adhere to PRISMA criteria. RESULTS: In agreement with a priori established protocol the search retrieved 2471 records leaving 479 results after duplicates removal. Eleven records result from title and abstract screening to meet the inclusion criteria; only 4 results are eligible for inclusion in the qualitative synthesis impeding meta-analysis. The qualitative analysis highlights the antinociceptive and anti-inflammatory efficacy of Δ8-tetrahydrocannabinol, cannabidiol and its derivative HU-308 and of new racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229. Moreover, CB2R agonists RO6871304 and RO6871085 and CB2R ligand HU910 provide evidence of anti-inflammatory efficacy. CB2 agonist HU308 reduces of 241% uveitis-induced leukocyte adhesion and changes lipidome profile. Methodological and design issues raise concern of risk of bias and the amount of studies is too small for generalization. Furthermore, the ocular pain model used can resemble only inflammatory but not neuropathic pain. CONCLUSIONS: The role of the endocannabinoid system in ocular pain is underinvestigated, since only two studies assessing the effects of cannabinoid receptors modulators on pain behavior and other two on pain-related inflammatory processes are found. Preclinical studies investigating the efficacy of cannabinoids in ocular inflammatory and neuropathic pain models are needed to pave the way for clinical translation.

Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain.

In complementary medicine, aromatherapy uses essential oils to improve agitation and aggression observed in dementia, mood, depression, anxiety and chronic pain. Preclinical research studies have reported that the essential oil obtained from bergamot (BEO) fruit (Citrus bergamia, Risso) modifies normal and pathological synaptic plasticity implicated, for instance, in nociceptive and neuropathic pain. Interestingly, recent results indicated that BEO modulates sensitive perception of pain in different models of nociceptive, inflammatory and neuropathic pain modulating endogenous systems. Thus, local administration of BEO inhibited the nociceptive behavioral effect induced by intraplantar injection of capsaicin or formalin in mice. Similar effects were observed with linalool and linalyl acetate, major volatile components of the phytocomplex, Pharmacological studies showed that the latter effects are reversed by local or systemic pretreatment with the opioid antagonist naloxone hydrochloride alike with naloxone methiodide, high affinity peripheral µ-opioid receptor antagonist. These results and the synergistic effect observed following systemic or intrathecal injection of an inactive dose of morphine with BEO or linalool indicated an activation of peripheral opioid system. Recently, in neuropathic pain models systemic or local administration of BEO or linalool induced antiallodynic effects. In particular, in partial sciatic nerve ligation (PSNL) model, intraplantar injection of the phytocomplex or linalool in the ipsilateral hindpaw, but not in the contralateral, reduced PSNL-induced extracellularsignal- regulated kinase (ERK) activation and mechanical allodynia. In neuropathic pain high doses of morphine are needed to reduce pain. Interestingly, combination of inactive doses of BEO or linalool with a low dose of morphine induced antiallodynic effects in mice. Peripheral cannabinoid and opioid systems appear to be involved in the antinociception produced by intraplantar injection of ß -caryophyllene, present in different essential oils including BEO. The data gathered so far indicate that the essential oil of bergamot is endowed with antinociceptive and antiallodynic effects and contribute to form the rational basis for rigorous testing of its efficacy in complementary medicine.

Cardiac surgery using only autologous blood for a patient with hereditary spherocytosis: a case report.

A 50-year-old man was admitted to our hospital for possible surgery. Echocardiogram showed severe calcification of the aortic valve, and cardiac catheter examination recorded a gradient greater than 150 mmHg across the valve. These results determined aortic valve replacement (AVR) to relieve the pressure-overloaded ventricle. Preoperative evaluations however, demonstrated anemia derived from hereditary spherocytosis (HS), an inherited hemolytic disorder. In order to avoid homologous blood transfusion, the following strategies were tried; 1) an iron supplement and an injection of recombinant human erythropoietin (rHuEPO); 2) pre- and perioperative autologous blood transfusion; and 3) an aggressive iron supplement just after the surgery. These raised the blood hemoglobin concentration to the criterion where autologous blood donation was started, and maintained the hemoglobin level stable, up to his discharge. In conclusion, bloodless cardiac surgery is possible for cases with anemia, and some strategies should be tried to raise and maintain the blood hemoglobin concentration well.

Venous aneurysm of the cephalic vein: report of a case.

We herein report the rare case of a 41-year-old Japanese woman in whom a venous aneurysm in the left cephalic vein was excised under local anesthesia. Histological examination revealed significant diminution in the number and size of muscle and elastic fibers in the aneurysm wall. Conceivably, a combination of endophlebohypertrophy and a congenital focal defect of the elastic and muscle fibers might have contributed to the development of this venous aneurysm.

Spinally-mediated behavioural responses evoked by intrathecal high-dose morphine: possible involvement of substance P in the mouse spinal cord.

Intrathecal (i.t.) administration of morphine in the spinal subarachnoid space of mice produced a severe hindlimb scratching followed by biting and licking. The onset of the scratching behaviour was observed 60-70 s after i.t. injection of morphine (60 and 90 nmol), and had a duration of 3-4 min. The morphine-induced behaviour was increased additively by i.t. co-administration of substance P (SP). This characteristic behavioural response was inhibited dose-dependently by i.t. co-administration of the tachykinin NK-1 receptor antagonists, sendide and CP-96,345. Significant antagonistic effects of SP (1-7), a putative antagonist for NK-1 receptors and [D-Phe7, D-His9]SP (6-11), a selective antagonist for SP receptors, were observed against the morphine-induced behaviour. Pretreatment with i.t. SP antiserum and i.t. capsaicin resulted in reduction of the response to morphine. I.t. administration of somatostatin (SOM) antiserum, cysteamine, a relatively selective depletor of SOM and cyclo-SOM, a SOM receptor antagonist, produced no inhibitory effect on the morphine-induced behaviour. These results demonstrate that a spinal system of neurones containing SP may be involved in elicitation of the behavioural episode following i.t. injection of morphine in mice.

Effects of an acute water load on plasma ANP and AVP, and renal water handling in hypothyroidism: comparison of before and after L-thyroxine treatment.

To assess whether atrial natriuretic peptide (ANP) and arginine vasopressin (AVP) participate in impaired water excretion in patients with hypothyroid states (HS), an oral acute water loading (WL) test (20 ml/kg.BW/45 min) was performed before and after L-thyroxine (T4) treatment in 5 hypothyroid patients. Plasma ANP, AVP, osmolality (Posm), total protein and renal water excretion were simultaneously determined, and these data were compared to the data from five normal subjects (NS). The impaired water excretion rate in HS was entirely improved in the euthyroid states (ES) after T4 therapy for at least 7 months. Plasma ANP in HS was lower than that in NS (5.9 +/- 0.9 vs. 16.5 +/- 3.6 pmol/L, P < 0.05), but increased after T4 treatment (21.2 +/- 5.7 pmol/L, P < 0.05). Plasma AVP in HS (1.6 +/- 0.5 pmol/L) showed a tendency to be lower than those in ES and NS (2.9 +/- 0.4 and 2.9 +/- 0.7 pmol/L), but did not respond to a fall in Posm after WL, unlike ES and NS. Significant positive correlations were noticed between Posm and plasma AVP in ES and NS, but not in HS. These results suggest that not only the impaired release and/or metabolisms of AVP and ANP, but also derangement of renal water and electrolytes handling might induce attenuation of CH2O formation in hypothyroid states.

A selective and extremely potent antagonist of the neurokinin-1 receptor.

Sendide [Tyr6,D-Phe7,D-His9]-substance P(6-11) has been examined by measurements of ligand binding to crude membrane fractions and by functional tests on the spinally mediated behavioral response. Sendide potently displaced [3H]-labeled substance P (SP) binding to mouse spinal cord membranes in a competitive manner. In vivo, sendide, intrathecally co-injected with SP, competitively antagonized SP-induced scratching, biting and licking. The behaviors elicited by physalaemin, septide and [Sar9, Met(O2)11]-SP were also reduced by co-administration of sendide. Large doses of sendide were needed to reduce the action of neurokinin A, D-septide, neurokinin B and eledoisin. The in vitro and in vivo pharmacological profile of sendide demonstrated that it is a selective and extremely potent antagonist of the neurokinin-1 receptor.

[Analysis of the determinant factors for open heart surgery without blood transfusion by the quantification theory--possibility of application of maximum surgical blood order schedule for open heart surgery].

In order to complete operations without blood transfusion we have chosen means of preoperative autologous blood saving and intraoperative autotransfusion, but we have not always achieved our purpose. We examined 29 patients (13 patients without blood transfusion and 16 with blood transfusion) to analyze the determinant factors as to whether open heart surgery without blood transfusion may be indicated or not, according to the quantification theory (type II) and to examine the possibility to apply the maximum surgical blood order schedule (MSBOS) for the open heart surgery by the quantification theory (type I). The analysis of determinant factors revealed hematocrit (Ht) value before saving of blood (more than 40%) as the best contributor of possibility of non-blood transfusion surgery, followed by the amount of blood loss during operation (less than 600 ml), the amount of saving blood (more than 800 ml), body weight (less than 70 kg), calculated Ht value on the beginning of cardiopulmonary bypass (CPB) (more than 24%), CPB time (less than 120 minutes) and the amount of postoperative blood loss (less than 600 ml). The prospective using blood volume at the operation was precisely calculated by the values of 4 preoperative factors, that is, the amount of saving blood, calculated Ht value on the beginning of CPB, CPB time and body weight. Therefore it is important to increase the amount of preoperative saving blood and decrease the amount of surgical bleeding in order to perform operations without blood transfusion, and is possible to apply the MSBOS for the open heart surgery.

Reversion of thyrotoxic atrial fibrillation in hypothyroid state after radioiodine treatment.

Twenty patients with thyrotoxic Basedow's disease complicated by atrial fibrillation lasting more than one month despite treatment with antithyroidal drugs were treated with radioiodine supplemented with an antithyroidal drug or inorganic iodine. We classified the 20 patients on the basis of atrial fibrillation reversion into two groups, one with reversion (group I) and the other without reversion (group II). In all 12 patients in group I, T4 and T3 decreased to hypothyroid levels in 3.2 +/- 1.3 months, and one month later all patients had their sinus rhythm restored while T4 and T3 remained below normal (2.6 +/- 1.1 micrograms/dl and 77.9 +/- 34.4 ng/dl, respectively). Although T4 and T3 also decreased within 3.5 +/- 1.8 months in all 8 patients in group II, one month later, atrial fibrillation persisted while T4 and T3 (10.4 +/- 5.3 micrograms/dl and 157.7 +/- 67.5 ng/dl, respectively) rose significantly compared to those in group I (P less than 0.001 and P less than 0.01, respectively). For reversion of atrial fibrillation it is important that the onset of hypothyroidism is rapidly induced by radioiodine and that hypothyroidism continues for at least one month.

Long-term high frequency transcutaneous electrical nerve stimulation (hi-TNS) in chronic pain. Clinical response and effects on CSF-endorphins, monoamine metabolites, substance P-like immunoreactivity (SPLI) and pain measures.

Eighteen patients with chronic pain syndromes of organic origin were treated by means of high frequency transcutaneous nerve stimulation (hi-TNS). The CSF levels of receptorassayable Fraction I and II endorphins, substance P-like immunoreactivity (SPLI), and the monoamine metabolites 5-HIAA, HVA and MOPEG were measured before and after one week of daily treatment. Furthermore, the effects on experimental pain measures were determined. The therapeutic effect was evaluated after 30 days and 3 months of treatment. Patients with low initial concentrations of endorphins in CSF, lower than those observed in healthy volunteers, tended to have the best response to hi-TNS. There were significant increases in Fraction I endorphins and SPLI in CSF, most pronounced in the patients who responded. There were no significant changes in 5-HIAA, HVA or MOPEG in CSF. However, in early responders, the serotonin metabolite 5-HIAA tended to decrease as contrasted to an increase in non-responders. The difference between the groups was statistically significant. Confirming our earlier studies, the therapy induced changes in pain measures showed a significant, positive correlation with increasing Fraction I endorphins in CSF. Our results suggest that hi-TNS induces central changes in the endorphinergic, serotonergic and possibly substance-P-ergic systems.

[Effect of elcatonin on experimental osteoporosis induced by ovariectomy and low calcium diet in beagles].

Effect of elcatonin, a synthesized analogue of eel calcitonin, on experimental osteoporosis in beagles induced by ovariectomy and a low calcium diet was studied. Twelve female beagles, 15-18 months old, were divided equally into 3 groups. The first group of beagles were ovariectomized and then fed a low calcium diet, Ca: 0.08%, (ovariectomy plus low Ca diet group); the second group was subjected to the same procedure and diet plus daily injection of elcatonin, 1.0 u/kg, i.m., (elcatonin group); and the third group was fed a standard diet, Ca: 1.36%, (control group) for 6 months. The undecalcified bone sections from the iliac crest were analyzed using histomorphometric methods following in vivo double labeling with Calcein. In the ovariectomy plus low Ca diet group, there were a decrease in trabecular bone volume and an increase in both resorption and formation surface of the trabeculae compared with the control group. These changes of trabecular bone volume and resorption surface were significantly prevented by daily injection of elcatonin. The increase of formation surface of trabeculae and mineral appositional rate was noted in the elcatonin group in comparison with the ovariectomy plus low Ca diet group. These results suggested that elcatonin could prevent bone loss caused by deficiency of sex hormone and dietary calcium.

Comparison of the antinociceptive effect between the cyclic dipeptide cyclo[Tyr(Et)-homoarginine] and the linear dipeptide Boc-Tyr(Et)-homoarginine-OMe in rats.

The antinociceptive effect of the cyclic dipeptide cyclo[Tyr(Et)- homoarginine] (C.TEHA) was examined utilizing the tail flick test and the digitus pinching test in rats in comparison with the linear dipeptide Boc-Tyr(Et)-homoarginine-OMe (B.TEHM). Though both dipeptides administered into the lateral, 3rd and 4th cerebroventricles produced antinociceptive effects equipotent to morphine, except for the 4th cerebroventricular administration of B.TEHM, the administration into the spinal subarachnoid space was without effect. The effect of B.TEHM was completely antagonized by the pretreatment of naloxone (i.p.) when administered into the 3rd cerebroventricle where its effect was demonstrated to be the most potent. However, naloxone had no significant effect on C.TEHA administered into the 3rd cerebroventricle in both tests. It was concluded that both dipeptides act on the upper brain stem, especially around the 3rd cerebroventricle. Moreover, it was also thought that the effect of B.TEHM may be involved in the brain opioid system, and that of C.TEHA can be produced via a naloxone-resistant opioid system or a non-opioid system.

Changes in ingestive behavior, serum glucose and free fatty acids concentrations in rats following intracerebroventricular injection of spermine.

We examined the changes in ingestive behavior, serum glucose (Glc) and free fatty acids (FFA) concentrations in male rats following intracerebroventricular (i.c.v.) injection of spermine (SPM). In satiated rats, over a 53.3 nmol of SPM suppressed feeding and drinking behavior in a dose-dependent manner. The median suppressive dose was 90.8 nmol for feeding behavior and 68.3 nmol for drinking behavior. Spermidine also suppressed ingestive behavior but the potency was appreciable weak compared to that of SPM, and the occurrence of the maximal suppression was observed 2-3 days later than that of SPM. The most significant anorexia and adipsia induced by SPM appeared between 16 and 36 hr after i.c.v. administration. SPM (180 nmol) produced a biphasic increase in serum Glc concentration. The 1st peak was at 1 hr and the other peak was 24 hr after the dosing. The same dose of SPM elevated serum FFA concentrations gradually, and the maximal increase appeared 24 hr after the injection. As less than a 120 nmol dose of SPM did not alter serum Glc and FFA concentrations, there seems to be no causal relation between SPM-induced anorexia, and changes in serum Glc and FFA concentrations. Nevertheless, the findings that a very small dose of SPM produced anorexia and adipsia support the possibility that SPM may play some functional role in the brain.

Effects of intracerebroventricular administration of aliphatic diamines on ingestive behavior in the rat.

We examined the pharmacological effects of intracerebroventricularly administered aliphatic diamines on ingestive behavior in male rats adapted to a 4 hr per day feeding and drinking schedule. 1,2-Ethanediamine (ETD), 1,3-propanediamine (PRD), 1,4-butanediamine (putrescine, PUT), 1,5-pentanediamine (cadaverine, CAD) and 1,6-hexanediamine (HED) suppressed feeding and drinking behavior in a dose-dependent manner, but not unless a relatively high dose (over 80 micrograms) was given. The approximate anorectic potency was HED greater than CAD divided by PUT greater than ETD greater than PRD. A sedation was also produced in fairly good parallel to these alterations in feeding and drinking behavior. Thus, there appears to be a relationship between the length of the carbon chain and the potency of the pharmacological action, and these inhibitory effects on feeding and drinking behavior are probably not due to a specific action on the regulatory system for ingestive behavior, but rather to a nonspecific action.

[Effects of diazepam on rage reaction elicited by the lateral hypothalamus (LH) and on single unit activities in the LH and the basal medial amygdaloid nucleus (Abm) in cats (author's transl)].

Effects of diazepam were examined on the whine reaction elicited by LH stimulation and on unit activities in the LH and Abm in cats. The spontaneous firing frequency of Abm neurons was 5 to 30 spikes/sec and in all 6 neurons isolated the firing frequency increased by non-nociceptive and/or clap-stimulation. Diazepam decreased the spontaneous firing frequency of all Abm neurons isolated and the increased firing frequency elicited by non-nociceptive and/or clap-stimulation was also depressed by diazepam. The spontaneous firing frequency of neurons in the LH was 4 to 5 spikes/sec and all 6 neurons isolated firing frequency increased by non-nociceptive stimulation. Only one of 6 neurons, however, was activated by clap-stimulation. Diazepam decreased the spontaneous firing frequency of all LH neurons. Out of 6 neurons responsive to non-nociceptive stimulation, 3 were also depressed by diazepam. The other neurons were not affected by diazepam. These results suggest that depressed action of diazepam on the whine reaction elicited by the LH stimulation may be related to the decrease of firing in the Abm and/or the LH by diazepam.

[Effects of diazepam on evoked potential recorded from basal medial amygdaloid nucleus, lateral hypothalamus and midbrain reticular formation (author's transl)].

The evoked potential in the lateral hypothalamus (LH) recorded by stimulation of basal medial amygdaloid nucleus (Abm) showed a triphasic pattern and diazepam (2 mg/kg, i. p.) decreased the late component. The evoked potential in the midbrain reticular formation (MRF) recorded by stimulation of Abm showed a fast component with a relatively short latency followed by a biphasic late component and diazepam decreased the late component. Though the evoked potential in the Abm recorded by stimulation of LH showed a triphasic pattern, diazepam had no influence on the amplitude. Diazepam increased markedly the amplitude of evoked potential in the MRF recorded by stimulation of LH. Diazepam was ineffective on the evoked potential in the Abm recorded by stimulation of MRF. Diazepam decreased markedly the late component of evoked potential in the LH recorded by stimulation of MRF. These results suggest that the depression of emotional behavior by diazepam may be particularly related to the fact that the evoked potential in the LH recorded by stimulation of Abm was decreased by diazepam.