The effects of kratom on restraint-stress-induced analgesia and its mechanisms of action.

ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa and its extracts are called kratom (dried leaves, extract). They contain several alkaloids with an affinity for different opioid receptors. They are used in traditional medicine for the treatment of different diseases, as a substitute by opiate addicts, and to mitigate opioid withdrawal symptoms. Apart from their medical properties, they are used to enhance physical endurance and as a means of overcoming stress. PURPOSE: The aim of this study was to determine the mechanisms underlying the effects of kratom on restraint-stress-induced analgesia which occurs during or following exposure to a stressful or fearful stimulus. METHODS: To gain further insights into the action of kratom on stress, we conducted experiments using restraint stress as a test system and stress-induced analgesia as a test parameter. Using transgenic mu opioid-receptor (MOR) deficient mice, we studied the involvement of this receptor type. We used nor-binaltorphimine (BNT), an antagonist at kappa opioid receptors (KOR), to study functions of this type of receptor. Membrane potential assay was also employed to measure the intrinsic activity of kratom in comparison to U50,488, a highly selective kappa agonist. RESULTS: Treatment with kratom diminished stress-induced analgesia in wildtype and MOR knockout animals. Pretreatment of MOR deficient mice with BNT resulted in similar effects. In comparison to U50,488, kratom exhibited negligible intrinsic activity at KOR alone. CONCLUSIONS: The results suggest that the use of kratom as a pharmacological tool to mitigate withdrawal symptoms is related to its action on KOR.

Research Resource: Real-Time Analysis of Somatostatin and Dopamine Receptor Signaling in Pituitary Cells Using a Fluorescence-Based Membrane Potential Assay.

Stable somatostatin analogues and dopamine receptor agonists are the mainstay for the pharmacological treatment of functional pituitary adenomas; however, only a few cellular assays have been developed to detect receptor activation of novel compounds without disrupting cells to obtain the second messenger content. Here, we adapted a novel fluorescence-based membrane potential assay to characterize receptor signaling in a time-dependent manner. This minimally invasive technique provides a robust and reliable read-out for ligand-induced receptor activation in permanent and primary pituitary cells. The mouse corticotropic cell line AtT-20 endogenously expresses both the somatostatin receptors 2 (sst2) and 5 (sst5). Exposure of wild-type AtT-20 cells to the sst2- and sst5-selective agonists BIM-23120 and BIM-23268, respectively, promoted a pertussis toxin- and tertiapin-Q-sensitive reduction in fluorescent signal intensity, which is indicative of activation of G protein-coupled inwardly rectifying potassium (GIRK) channels. After heterologous expression, sst1, sst3, and sst4 receptors also coupled to GIRK channels in AtT-20 cells. Similar activation of GIRK channels by dopamine required overexpression of dopamine D2 receptors (D2Rs). Interestingly, the presence of D2Rs in AtT-20 cells strongly facilitated GIRK channel activation elicited by the sst2-D2 chimeric ligand BIM-23A760, suggesting a synergistic action of sst2 and D2Rs. Furthermore, stable somatostatin analogues produced strong responses in primary pituitary cultures from wild-type mice; however, in cultures from sst2 receptor-deficient mice, only pasireotide and somatoprim, but not octreotide, induced a reduction in fluorescent signal intensity, suggesting that octreotide mediates its pharmacological action primarily via the sst2 receptor.

Microvascular decompression for trigeminal neuralgia in the elderly: long-term treatment outcome and comparison with younger patients.

OBJECTIVE: Multiple studies have proved that microvascular decompression (MVD) is the treatment of choice in cases of medically refractory trigeminal neuralgia (TN). In the elderly, however, the surgical risks related to MVD are assumed to be unacceptably high and various alternative therapies have been proposed. We evaluated the outcomes of MVD in patients aged older than 65 years of age and compared them with the outcomes in a matched group of younger patients. The focus was on procedure-related morbidity rate and long-term outcome. METHODS: This was a retrospective study of 112 patients with TN operated on consecutively over 22 years. The main outcome measures were immediate and long-term postoperative pain relief and neurological status, especially function of trigeminal, facial, and cochlear nerves, as well as surgical complications. A questionnaire was used to assess long-term outcome: pain relief, duration of a pain-free period, need for pain medications, time to recurrence, pain severity, and need for additional treatment. RESULTS: The mean age was 70.35 years. The second and third branches of the trigeminal nerve were most frequently affected (37.3%). The mean follow-up period was 90 months (range, 48-295 months). Seventy-five percent of the patients were completely pain free, 11% were never pain free, and 14% experienced recurrences. No statistically significant differences existed in the outcome between the younger and older patient groups. Postoperative morbidity included trigeminal hypesthesia in 6.25%, hypacusis in 5.4%, and complete hearing loss, vertigo, and partial facial nerve palsy in 0.89% each. Cerebrospinal fluid leak and meningitis occurred in 1 patient each. There were no mortalities in both groups. CONCLUSION: MVD for TN is a safe procedure even in the elderly. The risk of serious morbidity or mortality is similar to that in younger patients. Furthermore, no significant differences in short- and long-term outcome were found. Thus, MVD is the treatment of choice in patients with medically refractory TN, unless their general condition prohibits it.