Ketamine: repurposing and redefining a multifaceted drug.

This short review will highlight recent clinical and basic research that supports the therapeutic utility of ketamine as a rapid-acting, life-saving antidepressant and a versatile analgesic. After 50 years of use as a dissociative anesthetic and misuse as a street drug, ketamine has re-emerged as a useful off-label agent for ameliorating various types of pain and resistant depression. In addition to its ability to inhibit N-methyl-D-aspartate (NMDA) receptors, the diverse actions of ketamine might involve epigenetic mechanisms such as microRNA regulation.

Non-analgesic effects of opioids: neuroprotection in the retina.

Inadequate blood flow in the retina (ischemia) is a common cause of visual impairment and blindness. Retinal ischemia plays a pivotal role in a number of ocular degenerative diseases such as diabetic retinopathy, glaucoma, and retinal artery occlusion. The sequence of events by which ischemia leads to retinal degeneration are not completely understood, but likely involve both necrotic and apoptotic processes.

Opioid receptor-activation: retina protected from ischemic injury.

Purpose: In nonocular systems, activation of opioid receptors has been shown to ameliorate tissue damage induced by ischemic stress. The current study was an investigation of whether opioid receptors activated by endogenous or exogenous agonists can ameliorate ischemic retinal injury.

Methods: In an investigation of whether endogenous opioid receptor-activation reduces ischemic injury, the effects of the opioid antagonist naloxone (3 mg/kg; IP) on retinal neuroprotection induced by ischemic preconditioning (IPC) were evaluated.

Bremazocine: a kappa-opioid agonist with potent analgesic and other pharmacologic properties.

Bremazocine is a kappa-opioid receptor agonist with potent analgesic and diuretic activities. As an analgesic it is three- to four-times more potent than morphine, as determined in both hot plate and tail flick tests. Bremazocine and other benzomorphan analogs were synthesized in an effort to produce opiates with greater kappa-opioid receptor selectivity and with minimal morphine-like side effects.

Bremazocine increases C-type natriuretic peptide levels in aqueous humor and enhances outflow facility.

A relatively selective agonist of kappa opioid receptors (KOR), bremazocine (BRE), lowers intraocular pressure in rabbits, in part, by increasing natriuretic peptide levels in aqueous humor and by enhancing total outflow facility (TOF). Natriuretic peptide (NP) levels [atrial NP (ANP), brain NP (BNP), and C-type NP (CNP)] were measured in aqueous humor of rabbits either by radioimmunoassay or enzyme immunoassay. TOF was determined in rabbits by two-level constant pressure perfusion of the anterior chamber.

Delta-opioid agonist-stimulated inositol phosphate formation in isolated, rabbit iris-ciliary bodies: role of G(i/o) proteins and Gbetagamma-subunits.

Our laboratory has previously demonstrated the ability of kappa- and delta-opioid agonists to decrease aqueous flow rates and intraocular pressure of rabbits. The mechanisms by which these agents act in the ciliary body of the rabbit could involve inhibition of cAMP production, as well as increased generation of inositol phosphates (IPs). With regard to enhanced production of IPs, it has been suggested that their levels can be augmented by stimulation of phospholipase C via opioid receptors linked to either Galpha-subunits derived from Gq proteins or Gbetagamma-subunits derived from G(i/o)-proteins.

Changes in muscle proteins and spermidine content in response to unloading and clenbuterol treatment.

Anabolic agents such clenbuterol (Cb) are useful tools for probing the mechanisms by which muscles respond to disuse. Cb was examined under different loading conditions with respect to its effects on muscle mass, protein (myofibrillar and cytosolic), and spermidine content in mature male rats. Compared with control treatment, Cb significantly increased loaded and unloaded soleus, plantaris, and extensor digitorum longus (EDL) mass.

Pharmacological evidence of a role for prejunctional imidazoline (I(1)) receptors in ocular function.

Imidazoline and guanidiniun-substituted isoindoline compounds have been reported to demonstrate affinity for the putative imidazoline receptors (I(1)) and alpha-2 (alpha(2)) adrenoceptors. The purpose of this study was to determine the relative contribution of I(1) receptors to ocular actions of moxonidine (MOX) and brimonidine (BRIM) by utilizing relatively selective alpha(2) and I(1) antagonists. MOX, an alpha(2)/I(1) receptor agonist, BRIM, a selective alpha( 2) agonist, efaroxan (EFA), an I(1)/alpha(2) antagonist and rauwolscine (RAU), a relatively selective alpha(2) antagonist, were utilized to study alterations in sympathetically evoked contractions of the cat nictitating membrane (CNM).

Biodegradable calcium phosphate nanoparticles as a new vehicle for delivery of a potential ocular hypotensive agent.

The purpose of this study was to determine the efficacy of a newly prepared formulation containing biodegradable calcium phosphate nanoparticles (CAP) and 7-hydroxy-2-dipropyl-aminotetralin (7-OH-DPAT) in pigmented and non-pigmented rabbits using the surrogate end points of intraocular pressure (IOP) and aqueous flow rate. IOP (mmHg) was measured by utilizing a manometrically calibrated Mentor pneumatonometer. Rates of aqueous humor flow were measured with a Fluorotron Master by estimating the dilution rate of fluorescein.

Dynorphin modulates ocular hydrodynamics and releases atrial natriuretic peptide via activation of kappa-Opioid receptors.

The present study was designed to investigate the effect of the kappa opioid receptor (KOR) agonist, dynorphin A (Dyn), on aqueous humor dynamics (intraocular pressure (IOP), aqueous humor flow rate (AFR)), pupil diameter (PD) and atrial natriuretic peptide (ANP) levels in the aqueous humor of the rabbit. Topical and unilateral application of Dyn caused dose-related, bilateral reductions in IOP and AFR. An intermediate dose of Dyn (33 microg) caused bilateral mydriasis whereas a higher dose (100 microg) caused unilateral miosis.

Ocular hypotension induced by electroacupuncture.

The purpose of this study was to investigate the effects of electroacupuncture (EA) on aqueous humor dynamics in rabbits. EA stimulation was performed through two acupuncture needles placed in close proximity to the sciatic nerve. The sites of needle entry were anesthetized.

Effect of bremazocine, a kappa-opioid receptor agonist, on inositol phosphate formation in isolated iris-ciliary bodies.

The goal of the current study was to examine the effect of the kappa-opioid agonist, bremazocine (BRE), on inositol phosphate (IP) formation in the rabbit iris-ciliary body (ICB). Concentrations of BRE (10(-7) to 10(-5) M) augmented levels of IP. Incubation of ICBs with BRE (10(-6) M) produced a time-dependent increase in IP levels that peaked at 60 s and declined to basal levels by 5 min.

Muscle-specific effects of hindlimb suspension and clenbuterol in mature male rats.

Anabolic agents are useful tools for probing the mechanisms by which muscle fibers perceive and respond to disuse. beta(2)-Adrenergic agonists exert protective, and/or reparative, effects on atrophying muscle tissue. The effects of one such agent, clenbuterol (Cb), were examined on muscle mass, total protein content, and myofibrillar protein content in selected hindlimb muscles [adductor longus (ADL), extensor digitorum longus (EDL), plantaris (PLAN), soleus (SOL)] of mature male rats, under different loading conditions.

Naphazoline-induced neuroendocrine changes: increases in ANP and cGMP levels, but suppression of NE, 3H-NE, and cAMP levels in rabbit eyes.

The objective of this study was to determine whether naphazoline, an alpha 2 (alpha2)/imidazoline (I1) agonist, can alter endogenous levels of atrial natriuretic peptide (ANP) and norepinephrine (NE) in aqueous humor and cyclic nucleotide (cAMP, cGMP) accumulation and NE overflow in the iris-ciliary body (ICB) of the rabbit eye. Topical naphazoline (25, 75, and 250 microg) caused a dose-dependent elevation of the ANP levels (36, 54, and 137 pg/ml, respectively) in aqueous humor. This effect was antagonized by pretreatment with efaroxan, an antagonist of I1/alpha2 receptors.

Effect of hindlimb suspension and clenbuterol treatment on polyamine levels in skeletal muscle.

Polyamines are unbiquitous, naturally occurring small aliphatic, polycationic, endogenous compounds. They are involved in many cellular processes and may serve as secondary or tertiary messengers to hormonal regulation. The relationship of polyamines and skeletal muscle mass of adductor longus, extensor digitorum longus, and gastrocnemius under unloading (hindlimb suspension) conditions was investigated.

Inhibition of cAMP accumulation by kappa-receptor activation in isolated iris-ciliary bodies: role of phosphodiesterase and protein kinase C.

The present study was designed to examine the roles of protein kinase C (PKC) and phosphodiesterase (PDE) in modulating the action of kappa receptor stimulation on cAMP accumulation in isolated iris-ciliary bodies (ICBs) of New Zealand White rabbits. The kappa receptor agonist, (+/-)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine (BRL-52537) (BRL), and the PKC activator, phorbol 12,13-dibutyrate (PDBu), both caused a concentration-dependent inhibition of forskolin-stimulated cAMP production. The inhibitory effect of BRL on cAMP levels was significantly reduced in the presence of the selective kappa receptor antagonist, norbinaltorphimine (10(-6) M), but the effect of PDBu was not, thus supporting the involvement of kappa-opioid receptors in the response to BRL.