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.

Involvement of peripheral cannabinoid and opioid receptors in ß-caryophyllene-induced antinociception.

BACKGROUND: ß-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis. The present study investigated the contribution of peripheral cannabinoid (CB) and opioid systems in the antinociception produced by intraplantar (i.pl.) injection of BCP. The interaction between peripheral BCP and morphine was also examined. METHODS: The antinociceptive effect of i.pl. BCP was assayed by the capsaicin tests in mice. Antagonists for CB and opioid receptors, and antisera against ß-endorphin were injected peripherally prior to i.pl. injection of BCP. Morphine in combination with BCP was injected subcutaneously or intrathecally. RESULTS: The i.pl. injection of BCP dose-dependently attenuated capsaicin-induced nociceptive response. The antinociceptive effect produced by BCP was prevented by pretreatment with AM630, a selective CB2 receptor antagonist, but not by AM251, a selective CB1 receptor antagonist. Pretreatment with naloxone, an opioid receptor antagonist, and ß-funaltrexamine, a selective µ-opioid receptor antagonist, reversed the antinociceptive effect of BCP. Pretreatment with naloxone methiodide, a peripherally acting antagonist for opioid receptors and antisera against ß-endorphin, resulted in a significant antagonizing effect on BCP-induced antinociception. Morphine-induced antinociception was increased by a low dose of BCP. The increased effect of morphine in combination with BCP was antagonized significantly by pretreatment with naloxone. CONCLUSIONS: The present results demonstrate that antinociception produced by i.pl. BCP is mediated by activation of CB2 receptors, which stimulates the local release from keratinocytes of the endogenous opioid ß-endorphin. The combined injection of morphine and BCP may be an alternative in treating chemogenic pain.

[Left ventricular reconstruction on the beating heart with retrograde coronary perfusion for repair of a left ventricular aneurysm associated with aortic regurgitation: report of a case].

A 67-year-old male was undergoing hemodialysis for renal failure. He had carotid stenosis, multiple liver cysts with impaired liver function, and mild aortic regurgitation in addition to a left ventricular aneurysm with reduced left ventricular function. We used intraaortic balloon pumping with a view to maintaining cerebral and hepatic blood flow during extracorporeal circulation. However, this procedure risked increased regurgitation at the aortic valve. Therefore, after aortic cross-clamping, we performed the left ventricular reconstruction while cardiac pulsation was maintained by retrograde coronary perfusion using normothermic oxygenated blood. Coronary artery bypass grafting followed after the cross-clamp was released. The patient's postoperative progress was smooth and he was discharged on 14th postoperative day.

[Bronchioloalveolar carcinoma illustrating difficulties in diagnosis and determination of operative management; report of a case].

A 56-year-old male was admitted to our hospital to treat for an abnormal lung shadow. Computed tomography (CT) revealed the shadow with ground-glass opacity that was 30 mm in diameter at left S6 lesion. Although transbronchial lung biopsy had been performed, histological diagnosis could not be made. We had expected the tumor could not be resected completely with a partial lung resection. Additionally, he refused being done a lower lobectomy without a histological diagnosis. So we performed a S6+S* segmentectomy with No. 7-12 lymph node dissection. Although the intraoperative frozen section diagnosis was an atypical adenomatous hyperplasia, the tumor was finally diagnosed as bronchioloalveolar carcinoma (BAC) because of its nuclear atypia. We did not resect the residual part of left lower lobe because he refused the additional operation and might have histopathologically no residual tumor and lymph node metastasis. At present, he is alive without any evidence of recurrence.

Occurrence of substance P(1-7) in the metabolism of substance P and its antinociceptive activity at the mouse spinal cord level.

Substance P (SP), which is known as a pain transmitter or modulator in the spinal cord, was degraded by the synaptic membranes of the mouse spinal cord. The major metabolites of SP were phenylalanine, SP(1-6), SP(1-7), SP(1-9), SP(8-9) and SP(10-11). Degradation of SP was inhibited by a metal chelator, o-phenanthroline, and also by specific inhibitors of endopeptidase-24.11, thiorphan and phosphoramidon. In contrast, captopril (a specific inhibitor of angiotensin-converting enzyme), bestatin (a specific inhibitor of aminopeptidase) and Z-321 (a specific inhibitor of prolylendopeptidase) showed little effect on the degradation of SP. The accumulation of the major cleavage products was strongly inhibited by phosphoramidon and thirophan, as well as the initial cleavage of SP. Thus, endopeptidase-24.11 plays a major role in SP degradation in the mouse spinal cord. Additional in vivo experiments were performed to investigate the antinociceptive effect of SP(1-7), a major product of SP that was detected after incubation with spinal synaptic membranes. In the mouse tail-flick test, the intrathecal administration of SP(1-7) (1.0-4.0 pmol) increased tail-flick latency in a dose-dependent manner. These results suggest that degradation of SP by spinal endopeptidase-24.11 may lead to the formation of SP(1-7), which has an ability to produce antinociceptive effects at the mouse spinal cord level.

[Induction chemotherapy and radical resection for primary nonseminomatous mediastinal germ cell tumor (NSGCT); report of a case].

A 15-year-old male was admitted to our hospital for treatment of an anterior mediastinal tumor. The tumor was visualized by chest radiography 3 months prior to admission. Computed tomography (CT) revealed a heterogeneous solid tumor located in the anterior mediastinum. Although CT-guided needle biopsy had been performed twice, histologic diagnosis could not be confirmed. We believed this tumor to be nonseminomatous mediastinal germ cell tumor (NSGCT) and started intensive chemotherapy with cisplatin (CDDP) without histologic diagnosis because his serum AFP level was rapidly increasing. After 2 courses of chemotherapy, his serum AFP level returned to the normal range and surgical resection of the tumor with part of right lung was performed. Histopathological examination revealed that the tumor consisted of mature teratoma and yolk sac tumor. He underwent 1 course of chemotherapy post-operatively because a small number of viable cells were histopathologically recognized in the yolk sac component. At the time of writing, the patient is alive without any evidence of recurrence.

[Thoracoscopic segmentectomy of the left upper division in a patient with endobronchial hamartoma; report of a case].

A 71-year-old man was admitted to our hospital for treatment of an endobronchial tumor. Although he was asymptomatic and chest radiography showed no tumor shadow, bronchoscopic findings demonstrated an endobronchial tumor with a villous surface occluding the bronchus of the left upper division. Endobronchial resection was abandoned because we could not directly observe the cervix with a bronchoscope. In addition, because we could not diagnose the tumor histologically as benign by biopsy specimens, we elected to perform a segmentectomy of the left upper division. To reduce surgical stress, the operation was carried out using thoracoscopy. The tumor was finally diagnosed as endobronchial chondromatous hamartoma. The patient's postoperative course was uneventful. When endobronchial resection is not feasible, a less invasive surgical approach and method should be taken in patients with suspected endobronchial hamartoma.

[Re-dissection of aortic root without gelatin-resorcin-formalin (GRF) glue effect one year after aortic repair].

A 58-year-old man, who had undergone emergency graft replacement of ascending and total aortic arch using gelatin-resorcin-formalin (GRF) glue 1 year before, complained of progressive shortness of breath. Ultrasound cardiography revealed severe aortic regurgitation and dissecting aneurysm of aortic root. He underwent composite graft replacement with the aid of the right axillary artery perfusion and deep hypothermic circulatory arrest. The redissected brownish intima was identified in the area of noncoronary cusp. There was no special finding in the subsequent histopathological examination. The use of GRF glue for reconstructing the dissected aortic root is associated with a certain amount of risk of aortic wall redissection. Therefore, care should be taken to ensure proper use of GRF glue.

The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models.

MOTIVATION: Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS: We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY: The specification of SBML Level 1 is freely available from http://www.sbml.org/

[Cardiovascular surgery in patients with Marfan syndrome].

The natural history of patients with Marfan syndrome is depressing, however, cardiovascular surgery can improve the prognosis. We reviewed the results of this surgical procedure for 10 years. Fourteen Marfan patients underwent cardiovascular surgery for a total of 21 times. Hospital mortality was 4.8% (1 case died on the 105th day after entire thoraco-abdominal aortic replacement because of pyothorax and sepsis), and the 5- and 10-year Kaplan-Meier survival was 92.9% and 77.4% respectively. Reoperation free rate was 51.4% and 38.6% respectively. Cardiovascular surgery in Marfan syndrome can be performed with good result. Aggressive surgical management and close follow-up of patients who undergo surgery is important.

[Successful lingular segmentectomy using bronchoplasty in a patient with early hilar second primary lung carcinoma].

A 71-year-old man was admitted to our hospital with a small protrusive lesion at the lingular orifice of the left upper bronchus. He had undergone a right lower lobectomy and mediastinal dissection for lung carcinoma (large cell carcinoma, pT1N0M0) 14 months earlier. Early hilar squamous cell carcinoma was diagnosed by chest radiograph, CT and transbronchial biopsy. We performed a lingular segmentectomy with wedge resection of the left upper bronchus and N 1 lymph node dissection. The tumor was histopathologically diagnosed as early hilar second primary lung carcinoma. The patient's postoperative course was uncomplicated. At present, he is alive with good respiratory condition and without any evidence of recurrence. Segmentectomy is appropriate for a patient with contralateral second primary lung carcinoma as well as a patient with early hilar lung carcinoma. Bronchoplasty seems to increase the likelihood that such a patient will be a candidate for segmentectomy.

[Long-term results of the operation for the aortic arch aneurysm].

Between October, 1991, and October, 2001, 60 patients underwent aortic arch replacement with or without an aortic arch branched graft for atherosclerotic arch aneurysms. Their mean age was 70.1 +/- 8.6 years. Eight (13.3%) patients were operated on an emergency basis because of rupture or impending rupture of aneurysms. All operations were performed with hypothermic extracorporeal circulation. Selective cerebral perfusion for cerebral protection during aortic arch repair and systemic circulatory arrest during distal graft anastomosis was used in 56 patients. Mean selective cerebral perfusion time was 86.1 +/- 12.1 minutes. A total of 14 concomitant procedures were done. Overall in-hospital mortality was 3.3%. Postoperative temporary and permanent neurologic dysfunction were 1.6% and 1.6%. Long-term follow-up was 100% complete. There were 6 late deaths with the cumulative survival rate was 74.6 +/- 8.8%. A subsequent aortic operation was necessary for the treatment of an aortic abnormality distal to the arch in 6 patients. Reoperation free rate was 85.2 +/- 5.8%. In conclusion, cerebral protective effect of antegrade selective cerebral perfusion and total arch replacement with an aortic arch branched graft could substantially reduce in-hospital mortality and postoperative neurologic dysfunction and a satisfactory long-term results could be obtain in patients with atherosclerotic arch aneurysms.

Pronociceptive effects of nociceptin/orphanin FQ (13-17) at peripheral and spinal level in mice.

The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is reported to be metabolized by aminopeptidase N and endopeptidase 24.15. In the present study, N/OFQ C-terminal fragments elicited nociceptive responses in the peripheral nociceptors and in the spinal cord, whereas N-terminal fragments had no significant nociception. The nociceptive effect of N/OFQ (13-17) was most potent and remained unchanged in N/OFQ peptide receptor (NOPR) gene knockout mice, indicating that N/OFQ (13-17)-induced nociception is mediated through a novel mechanism independent of the activation of NOPR. This finding was further confirmed by in vitro guanosine 5'-O-(3-[35S]thio)triphosphate binding experiments, in which N/OFQ (13-17) showed no significant binding activity in baculovirus/sf21 cells expressing NOPR together with G protein alpha(i)1-, beta1-, and gamma2-subunits, whereas N/OFQ showed stimulation in a concentration-dependent manner. On the other hand, although a typical bell-shaped dose-response relationship was observed with a wide range of N/OFQ doses in both peripheral and central nociception tests, N/OFQ (13-17) did not show bell-shaped dose-response relationship in the central nociception test. This finding indicates that N/OFQ (13-17), in contrast to N/OFQ, lacks the postsynaptic antinociceptive actions modulating substance P signaling in the spinal cord. Together, our results suggest that C-terminal fragments of N/OFQ have potent nociceptive actions, and N/OFQ (13-17) could have the potential to mediate its actions through a novel mechanism independent of the activation of NOPR in the nociceptors and in spinal synapses.

Differential antinociceptive effects induced by intrathecally administered endomorphin-1 and endomorphin-2 in the mouse.

Two highly selective mu-opioid receptor agonists, endomorphin-1 and endomorphin-2, have been identified and postulated to be endogenous ligands for mu-opioid receptors. Intrathecal (i.t.) administration of endomorphin-1 and endomorphin-2 at doses from 0.039 to 5 nmol dose-dependently produced antinociception with the paw-withdrawal test. The paw-withdrawal inhibition rapidly reached its peak at 1 min, rapidly declined and returned to the pre-injection levels in 20 min. The inhibition of the paw-withdrawal responses to endomorphin-1 and endomorphin-2 at a dose of 5 nmol observed at 1 and 5 min after injection was blocked by pretreatment with a non-selective opioid receptor antagonist naloxone (1 mg/kg, s.c.). The antinociceptive effect of endomorphin-2 was more sensitive to the mu (1)-opioid receptor antagonist, naloxonazine than that of endomorphin-1. The endomorphin-2-induced paw-withdrawal inhibition at both 1 and 5 min after injection was blocked by pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine (10 mg/kg, s.c.) or the delta(2)-opioid receptor antagonist naltriben (0.6 mg/kg, s.c.) but not the delta(1)-opioid receptor antagonist 7-benzylidine naltrexone (BNTX) (0.6 mg/kg s.c.). In contrast, the paw-withdrawal inhibition induced by endomorphin-1 observed at both 1 and 5 min after injection was not blocked by naloxonazine (35 mg/kg, s.c.), nor-binaltorphimine (10 mg/kg, s.c.), naltriben (0.6 mg/kg, s.c.) or BNTX (0.6 mg/kg s.c.). The endomorphin-2-induced paw-withdrawal inhibition was blocked by the pretreatment with an antiserum against dynorphin A-(1-17) or [Met(5)]enkephalin, but not by antiserum against dynorphin B-(1-13). Pretreatment with these antisera did not affect the endomorphin-1-induced paw-withdrawal inhibition. Our results indicate that endomorphin-2 given i.t. produces its antinociceptive effects via the stimulation of mu (1)-opioid receptors (naloxonazine-sensitive site) in the spinal cord. The antinociception induced by endomophin-2 contains additional components, which are mediated by the release of dynorphin A-(1-17) and [Met(5)]enkephalin which subsequently act on kappa-opioid receptors and delta(2)-opioid receptors to produce antinociception.

Hyperosmotic stimuli induces recruitment of aquaporin-1 to plasma membrane in cultured rat peritoneal mesothelial cells.

Aquaporin-1 (AQP-1) has been reported to play an important role in peritoneal dialysis. To determine the precise mechanism involved, we used cultured rat peritoneal mesothelial cells (RPMCs) to examine the translocation of AQP-1 to the plasma membrane induced by hyperosmotic stimuli. Cultured RPMCs obtained from male Sprague-Dawley rats were incubated at room temperature in Dulbecco modified Eagle medium/F12 (DMEM/F12) with and without glucose or mannitol as the hyperosmotic stimulus. The plasma membrane was then extracted by the Percoll gradient method. Finally, the abundance AQP-1 molecules in the membrane fraction was determined by Western blot analysis. Significant enhancement of AQP-1 abundance (p < 0.05) was observed within 2.5 minutes of the addition of 5% glucose to the medium. The increase was sustained in its abundance through 15 minutes. Abundance of AQP-1 was also increased (p < 0.05) by the addition of 5% mannitol. These results suggest that hyperosmotic stimuli could generate increased AQP-1 abundance in the plasma membrane by translocation of AQP-1 protein from recycling endosomes or early endosomes to the plasma membrane, rather than by protein synthesis via newly expressed mRNA. The latter mechanism would be expected to take more time.

[Detection of visceral ischemia with doplex scanning method of mesenteric arteries: in patients with acute type B aortic dissection].

Between March, 1997 and January, 1999, 11 patients with acute type B aortic dissection underwent doplex scanning evaluation of mesenteric arteries for the early detection of visceral ischemia. Peak systolic velocity (PSV) of the celiac artery (CeA) and superior mesenteric artery (SMA) was measured on their admission. Mean PSV of CeA in the non-ischemic group (8 patients) and in the ischemic group (3 patients) was 1.66 +/- 0.34 m/sec and 3.60 +/- 0.49 m/sec (p = 0.0481), respectively. Mean PSV of the SMA in the non-ischemic group and in the ischemic group was 1.93 +/- 0.52 m/sec and 3.33 +/- 0.37 m/sec (p = 0.00768), respectively. All patients with PSV of the mesenteric arteries above 3.00 m/sec presented visceral ischemia that required emergency operation. If PSV of the mesenteric arteries exceeds 3.00 m/sec, urgent surgical repair should be considered.

[A case of mucosa associated lymphoid tissue (MALT) lymphoma].

We examined a 49-year-old man, who was referred to our hospital for resection of abnormal findings on the X-ray. Before hospital admission, he was performed TBLB and aspiration biopsy in other hospital, but the results was not decided diagnosis. Because the possibility of the lung cancer was not completely nagated, we performed the tumor resection (partial pulmonary resection) in use of thoracoscopy. The tumor was diagnosed as a MALT (mucosa associated lymphoid tissue) lymphoma at histologically and immunohistologically (CD 79), and resectable lymph node did not detected malignant cell. He has had no evidence of recurrence for 5 months after the operation.

[Endoventricular circular patch plasty (dor operation) for postinfarction left ventricular aneurysm and ischemic cardiomyopathy].

The determination of purse-string suture line is one of the most important point in endoventricular circular patch plasty (Dor operation) for postinfarction left ventricular aneurysm (LVAN), especially for ischemic cardiomyopathy (ICM). We suggest following three points to decide appropriate suture line. First, the purse-string suture on the basal side should be placed on the 1-2 cm level under diagonal branch. Secondly, lateral wall should not be over excluded to maintain left ventricular function. And the third, akinetic or dyskinetic lesion of apex and septal wall should be excluded as much as possible. Nine cases of five LVAN and four ICM were underwent Dor operation in our institute from Dec. 1999 to Jan. 2000. All patients were weaned from cardiopulmonary bypass easily except one patient, who was operated under IABP support, because of his preoperative severe heart failure. All patients recovered well without any serious complications and postoperative left ventricular graphies were satisfactory. Left ventricular ejection fraction and stroke volume index were increased from 34 +/- 17 to 55 +/- 16% and from 38 +/- 7 to 47 +/- 6 ml/m2, end-diastric and systric volume index decreased from 141 +/- 37 to 88 +/- 19 ml/m2 and from 96 +/- 41 to 41 +/- 23 ml/m2 respectively. The Dor procedure adopted our idea led to satisfactory result in hemodynamic and also in morphologic study.