Kratom Use Within the Context of the Evolving Opioid Crisis and the COVID-19 Pandemic in the United States.

Kratom (Mitragyna speciosa, Korth.) is an evergreen tree that is indigenous to Southeast Asia. When ingested, kratom leaves or decoctions from the leaves have been reported to produce complex stimulant and opioid-like effects. For generations, native populations in Southeast Asia have used kratom products to stave off fatigue, improve mood, alleviate pain and manage symptoms of opioid withdrawal. Despite the long history of kratom use in Asia, it is only within the past 10-20 years that kratom has emerged as an important herbal agent in the United States, where it is being used for the self-treatment of pain, opioid withdrawal symptoms, and mood disorders. The increase in the use of kratom in the United States has coincided with the serious epidemic of opioid abuse and dependence. Since 2015, efforts to restrict access to prescription opioids have resulted in a marked increase in the use of "street" opioids such as heroin and illicit fentanyl. At the same time, many patients with chronic pain conditions or opioid use disorder have been denied access to appropriate medical help. The lack of access to care for patients with chronic pain and opioid use disorder has been magnified by the emergence of the COVID-19 pandemic. In this report, we highlight how these converging factors have led to a surge in interest in kratom as a potential harm reduction agent in the treatment of pain and opioid use disorder.

Effects of trans- versus cis-resveratrol on adrenergic contractions of the rat tail artery and role of endothelium.

The health benefits of the natural polyphenol trans-resveratrol may play an important role in preventing a variety of diseases. Resveratrol has been shown to reduce blood pressure and improve metabolic diseases such as type 2 diabetes mellitus and obesity. Our previous studies examined the role of K+ channels in the vasorelaxation responses to trans-resveratrol in the rat tail artery. During these studies, we uncovered a novel transient contraction prior to the sustained relaxation effect of trans-resveratrol. Thus, the purpose of this study was to determine the role of the endothelium in these vascular contraction and relaxation responses to trans-resveratrol. We additionally sought to determine if the cis-isomer of resveratrol exerts any of the same vascular effects as the trans-isomer. The vascular responses to trans-resveratrol were examined in rat tail arteries with intact or denuded endothelium over a 2-hr period. Additionally, the vascular responses to trans- and cis-resveratrol were compared in rat tail arteries with intact endothelium. Both the transient contractile response and the persistent relaxation response to trans-resveratrol were similar in the arterial rings with intact or denuded endothelium. There was a significant correlation between the initial contraction-enhancing action of trans-resveratrol and the magnitude of the sustained relaxation for vessels with both intact and denuded endothelium. Moreover, we demonstrated that cis-resveratrol produced a significantly greater relaxation response as compared to trans-resveratrol without the initial contractile response. These data demonstrate the role of the vascular smooth muscle in the vascular responses to resveratrol and the potential clinical benefits of the cis-isomer of resveratrol as compared to the trans-isomer.

Differential effects of long-term slow-pressor and subpressor angiotensin II on contractile and relaxant reactivity of resistance versus conductance arteries.

Vascular reactivity was evaluated in three separate arteries isolated from rats after angiotensin II (Ang II) was infused chronically in two separate experiments, one using a 14-day high, slow-pressor dose known to produce hypertension and the other using a 7-day low, subpressor but hypertensive-sensitizing dose. There were three new findings. First, there was no evidence of altered vascular reactivity in resistance arteries that might otherwise explain the hypertension due to the high Ang II or the hypertensive-sensitizing effect of the low Ang II dose. Second, the high Ang II dose exerted a novel differential effect on arterial contractile responsiveness to the sympathetic neurotransmitter, norepinephrine, depending on the level of sympathetic innervation. It clearly enhanced that responsiveness in the sparsely innervated aorta but not in small mesenteric resistance arteries or the proximal (conductance) portion of the caudal artery, both of which are densely innervated. This suggests that the increased expression of alpha adrenergic receptors after long-term exposure to Ang II as previously reported for aortic smooth muscle, is prevented in densely innervated arteries, likely due to long-term Ang II-mediated increase in sympathetic neural traffic to those vessels. Third, the same high dose of Ang II impaired aortic relaxation in response to the nitric oxide (NO) donor nitroprusside without impairing aortic endothelium-dependent relaxation. NO is the main relaxing substance released by aortic endothelium. Accordingly, it is possible that this dose of Ang II is also associated with enhanced release of and/or enhanced smooth muscle responsiveness to other endothelial relaxing substances in a compensatory capacity.

Resveratrol can both enhance and relax adrenergic contractions of the rat tail artery.

Our aims were to determine 1) if resveratrol's vasorelaxant action is greater in the distal (resistance) versus proximal (conductance) portion of the rat tail artery, and 2) if it can be blocked by agents known to block different potassium (K) channels in arterial smooth muscle. We found that its half-maximally effective concentration values were essentially identical (25 ± 3 versus 27 ± 3 µM) for relaxing adrenergically-precontracted rings prepared from distal versus proximal tissues. This does not confirm a previous report of greater relaxation in resistance versus conductance arteries. We also found that its relaxation could not be blocked by any of seven different K channel blockers. However, we uncovered a novel unanticipated action not yet reported. In half our arterial ring preparations, resveratrol transiently enhanced adrenergically-induced precontractions beginning well before its sustained relaxant effect became apparent. This action provides the first reasonable explanation for previously unexplained increases in arterial pressures observed during acute intravenous administration of resveratrol to animal models of traumatic ischemic tissue injury, in which hypotension is often present and in need of correction. Also unanticipated, this same transient enhancement of adrenergic contraction was notably inhibited by some of the same K channel blockers (particularly tetraethylammonium and glibenclamide) that failed to influence its relaxant effect. Although we do not rule out smooth muscle as a possible site for such a paradoxical finding, we suspect resveratrol could also be acting on K-selective mechano-sensitive ion channels located in the endothelium where they may participate in release of contracting factors.

Sildenafil does not enhance but rather attenuates vasorelaxant effects of antidiabetic agents.

Type 2 diabetic men commonly experience erectile dysfunction for which phosphodiesterase-5 (PDE5) inhibitors like sildenafil (Viagra) are often recommended. By preventing degradation of cyclic guanosine monophosphate (cGMP) in vascular smooth muscle, these inhibitors also enhance arterial vasorelaxant effects of nitric oxide donors (which stimulate cGMP synthesis). In the present work, we confirmed this enhancing effect after co-administration of sildenafil with nitroprusside to freshly-isolated rat tail arterial tissues. However, in the same tissues we also observed that sildenafil does not enhance but rather attenuates vasorelaxant effects of three commonly-used antidiabetic drugs, i.e. the biguanide metformin and the thiazolidinediones pioglitazone and rosiglitazone. Indeed, sildenafil completely blocked vasorelaxant effects of low concentrations of these drugs. In addition, we found that this same novel anti-vasorelaxant interaction of sildenafil with these agents was abolished by either 1) omitting extracellular glucose or 2) inhibiting specific smooth muscle glycolytic pathways; pathways known to preferentially utilize extracellular glucose to fuel certain adenosine triphosphate (ATP)-dependent ion transporters: e.g. ATP-sensitive K channels, sarcoplasmic reticulum Ca-ATPase, plasma membrane Ca-ATPase and Na/K-ATPase. Accordingly, we suspect that altered activity of one or more of these ion transporters mediates the observed attenuating (anti-vasorelaxant) interaction of sildenafil with the antidiabetic drugs. The present results are relevant because hypertension is so common and difficult to control in Type 2 diabetes. The present data suggest that sildenafil might interfere with the known antihypertensive potential of metformin and the thiazolidinediones. However, they do not suggest that it will interact with them to cause life-threatening episodes of severe hypotension, as can occur when it is co-administered with nitrates.

Chronic social isolation in the prairie vole induces endothelial dysfunction: implications for depression and cardiovascular disease.

Humans with depression show impaired endothelium-dependent vasodilation; one recent demonstration of which was in the form of a reduced acetylcholine (ACh)-induced relaxation of adrenergically-precontracted small arteries biopsied from older depressed patients. Results from such uses of ACh in general have been validated as the most predictive marker of endothelium-related cardiovascular diseases. Accordingly, we examined vascular reactivity to ACh in the socially isolated prairie vole, a new animal model relevant to human depression and cardiovascular disease. Thoracic aortas were carefully dissected from female prairie voles after one month of social isolation (versus pairing with a sibling). Only aortas that contracted to the adrenergic agent phenylephrine (PE) and then relaxed to ACh were evaluated. Among those, ACh-induced relaxations were significantly reduced by social isolation (p<0.05), with maximum relaxation reaching only 30% (of PE-induced precontraction) compared to 47% in aortas from paired (control) animals. Experimental removal of the endothelium from an additional set of aortic tissues abolished all ACh relaxations including that difference. In these same tissues, maximally-effective concentrations of the nitric oxide-donor nitroprusside still completely relaxed all PE-induced precontraction of the endothelial-free smooth muscle, and to the same degree in tissues from isolated versus paired animals. Finally, in the absence of PE-induced precontraction ACh did not relax but rather contracted aortic tissues, and to a significantly greater extent in tissues from socially isolated animals if the endothelium was intact (p<0.05). Thus, social isolation in the prairie vole may (1) impair normal release of protective anti-atherosclerotic factors like nitric oxide from the vascular endothelium (without altering the inherent responsiveness of the vascular smooth muscle to such factors) and (2) cause the endothelium to release contracting factors. To our knowledge this is the first demonstration of this phenomenon in an animal model of depression induced solely by social isolation. These findings have implications for understanding mechanisms involved in depression and cardiovascular disease.

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil.

Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARalpha). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPAR alpha may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 microM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 microM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.

Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist.

BACKGROUND: A high rate of comorbidity exists between mood disorders and alcohol dependence. Furthermore, both ketamine, a dissociative anesthetic with a recently described rapid-onset antidepressant effect, and ethanol are N-methyl-D-aspartate (NMDA) receptor antagonists. Previous investigations of healthy individuals with a family history of alcohol dependence have found that these individuals have an attenuated response to ketamine's perceptual disturbance and dysphoric effects similar to that found in individuals with a self-reported history of alcohol dependence. This study investigated whether a family history of alcohol dependence influences ketamine's initial antidepressant effect. METHODS: Twenty-six subjects with DSM-IV treatment-resistant major depression were given an open-label intravenous infusion of ketamine hydrochloride (.5 mg/kg) and rated using various depression scales at baseline, 40, 80, 120, and 230 min postinfusion. The primary outcome measure was Montgomery-Asberg Depression Rating Scale (MADRS) scores. RESULTS: Subjects with a family history of alcohol dependence showed significantly greater improvement in MADRS scores compared with subjects who had no family history of alcohol dependence. CONCLUSIONS: A family history of alcohol dependence appears to predict a rapid initial antidepressant response to an NMDA receptor antagonist.

Attenuation by 4-aminopyridine of delayed vasorelaxation by troglitazone.

Troglitazone and other thiazolidinediones (TZDs) are thought to relax arterial smooth muscle by directly inhibiting calcium channels in smooth muscle cell membranes. However, until recently such inhibition was only examined acutely, ie, within only seconds or minutes after administration of these agents to arterial smooth muscle preparations. Recently, a novel experiment was reported in which troglitazone caused a 2-phase relaxation of perfused resistance arteries, namely, an acute relaxation (within the first 20 minutes of treatment), which was blocked by a nonselective calcium channel blocker and a delayed relaxation (after 2 hours), which was not. We sought to determine if any of the 4 major potassium (K) channels in vascular smooth muscle play a role in the delayed relaxation. We incubated vascular contractile rings prepared from ventral tail arteries of rats with physiological buffer containing either 0 or 4 micromol/L troglitazone for 3 hours (4 micromol/L is typical of plasma levels from diabetic patients). Different K channel inhibitors (1 mmol/L 4-aminopyridine [4AP]; 1 mmol/L tetraethylammonium [TEA]; 5 micromol/L glyburide; 20 micromol/L barium) were coadministered with each level of troglitazone in additional preparations. Then these arterial rings were contracted with either norepinephrine (NE), arginine vasopressin (AVP), or high-K buffer. All contractions were significantly relaxed by troglitazone (P <.05). Only 4AP significantly attenuated troglitazone's relaxation of NE and AVP contractions (P <.05), though not high-K-induced contractions. TEA, glyburide, and barium had no such influence. Thus, for both adrenergic (NE) and nonadrenergic (AVP) contractions, the delayed arterial vasorelaxation by troglitazone may be mediated at least in part by activation of 4AP-sensitive K channels. Furthermore, the specific subtype of the channels involved is most likely those bound in the outer cell membrane where their effectiveness in terms of mediating relaxation would depend on an intact transmembrane K ion gradient.