alpha(2)-adrenergic agonists for regional anesthesia - A clinical review of clonidine (1984-1995)

We have studied the responses to electrical and chemical stimulation of the ventrolateral medulla in the chloralose-anesthetized, paralyzed, artificially ventilated rat Locations of most active pressor responses were compared to regions containing neurons labeled immunocytochemically for phenylethanolamine N-methyltransferase (PNMT), the enzyme catalyzing the synthesis of adrenaline Elevations of arterial pressure (+816 +/- 25 mm Hg) and cardioacceleration (+73 +/- 136 bpm) were elicited with low current (5 times threshold of 95 +/- 11 microA) electrical stimulation in a region of rostral ventrolateral medullary reticular formation we have termed the nucleus reticularis rostroventrolateralis (RVL) Electrical stimulation of the RVL increased plasma catecholamines (168-fold for adrenaline, 53-fold for noradrenaline, and 19-fold for dopamine) and vasopressin (17-fold before spinal transection, 47-fold after) The location of the most active pressor region in the ventrolateral medulla corresponded closely with the location of C1 adrenaline-synthesizing (PNMT-containing) neurons In addition, the location of the most active pressor region in the dorsomedial medulla corresponded with the location of a bundle of PNMT-containing axons Unilateral injections into the RVL of the excitatory amino acid monosodium L-glutamate (50 pmol to 10 nmol), but not saline, caused transient dose-dependent and topographically specific elevations (maximum +716 +/- 49 mm Hg) of arterial blood pressure and tachycardia Injections of the rigid structural analogue of glutamate, kainic acid, caused large, prolonged (at least 15 min) pressor responses and tachycardia Unilateral injections of the inhibitory amino acid gamma-aminobutyric acid (GABA) into the RVL caused transient dose-dependent hypotension (maximum -408 +/- 66 mm Hg) and bradycardia, whereas the specific GABA antagonist bicuculline caused prolonged (10 to 20 min) elevations (+642 +/- 68 mm Hg) of arterial pressure and tachycardia By contrast, injections of the glycine antagonist strychnine had no significant effect Bilateral injections of the neurotoxin, tetrodotoxin, dropped arterial pressure to low levels (517 +/- 47) not changed by subsequent spinal cord transection at the first cervical segment (525 +/- 62) We propose the following (1) Neurons within the RVL, most probably C1 adrenaline-synthesizing neurons, exert an excitatory influence on sympathetic vasomotor fibers, the adrenal medulla, and the posterior pituitary (2) These neurons are tonically active and under tonic inhibitory control, in part via GABAergic mechanisms--perhaps via the nucleus of the solitary tract (NTS)(ABSTRACT TRUNCATED AT 400 WORDS)

https://www.jneurosci.org/content/jneuro/4/2/474.full.pdf

Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin

Distribution of α2 agonist binding sites in the rat and human central nervous system: Analysis of some functional, anatomic correlates of the pharmacologic effects of clonidine and related adrenergic agents

• Yohimbine, an α2-adrenergic receptor antagonist that increases noradrenergic function, was administered to 20 healthy subjects and 39 drug-free patients with agoraphobia and panic attacks. Following drug administration, changes in plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG), BP, pulse rate, and subjective ratings of feelings and somatic symptoms were examined during a four-hour period. Yohimbine produced significantly greater increases in patient-rated anxiety, nervousness, palpitations, hot and cold flashes, restlessness, tremors, piloerection, and sitting systolic BP in the total patient group compared with healthy subjects. There were significant correlations between the yohimbine-induced rise in plasma MHPG level and patient-rated anxiety and nervousness and the frequency of reported panic attacks. Patients experiencing frequent panic attacks (>2.5 per week) had a significantly greater plasma MHPG response to yohimbine than the healthy subjects and patients having less frequent panic attacks. These observations support a hypothesis of increased sensitivity to augmented noradrenergic function in anxiety states associated with panic, and they suggest that impaired presynaptic noradrenergic neuronal regulation may exist in patients with frequent panic attacks.

Noradrenergic Function in Panic Anxiety: Effects of Yohimbine in Healthy Subjects and Patients With Agoraphobia and Panic Disorder

Although the vast majority of patients with cancer pain receive effective analgesia from standard therapy, a few patients, particularly those with neuropathic pain, continue to experience severe pain despite large doses of systemic or intraspinal opioids. Animal studies suggest intraspinal alpha 2-adrenergic agonists may be effective in such cases. Eighty-five patients with severe cancer pain despite large doses of opioids or with therapy-limiting side effects from opioids were randomized to receive, in a double-blind manner, 30 micrograms/h epidural clonidine or placebo for 14 days, together with rescue epidural morphine. Pain was assessed by visual analog score (VAS), McGill Pain Questionnaire, and daily epidural morphine use. Success was defined as a decrease in either morphine use of VAS pain, with the alternative variable either decreasing or remaining constant. Blood pressure, heart rate, and degree of nausea and sedation were monitored. Successful analgesia was more common with epidural clonidine (45%) than with placebo (21%). This was particularly prominent in those with neuropathic pain (56% vs. 5%). Pain scores were lower at the end of the treatment period in patients with neuropathic pain treated with clonidine rather than placebo, whereas morphine use was unaffected. Clonidine, but not placebo, decreased blood pressure and heart rate. Hypotension was considered a serious complication in 2 patients receiving clonidine and in 1 patient receiving placebo. This study confirms the findings from previous animal studies which showed the effective, potent analgesic properties of intraspinal alpha 2-adrenergic agonists and suggests that epidural clonidine may provide effective relief for intractable cancer pain, particular of the neuropathic type.

Epidural clonidine analgesia for intractable cancer pain

The neuropil surrounding sympathetic preganglionic neurons (SPNs) receives an abundant catecholaminergic innervation originating from the brain stem. The effect of catecholamines (CA) released at this spinal level on the activity of SPNs is still controversial as is the extent to which this particular CA transmission is affected by central antihypertensive drugs, such as clonidine and alpha-methyldopa. The present study was initiated, therefore, to determine the effects of iontophoretic applications of CAs and clonidine on the discharges of identified SPNs and to determine the type of receptor mediating the action of these compounds. Extracellular recordings were made with five- or six-barrel electrodes in 20 pigeons anesthetized with urethane, artificially ventilated, and immobilized. Data were obtained on 83 SPNs localized in the three first thoracic segments and identified on the basis of constancy of antidromic activation latency and collision. All of the cells sampled were inhibited by the application of low iontophoretic currents of clonidine and by a series of CAs, including alpha-methylnorepinephrine, epinephrine, and phenylephrine. For each compound, the amount of charge necessary to decrease the level of cell firing to 50% of control was calculated. Using this value as an index of drug potency, the following rank order could be determined: clonidine greater than alpha-methylnorepinephrine greater than epinephrine greater than norepinephrine greater than phenylephrine. The inhibitory effects of both clonidine and norepinephrine were antagonized by iontophoretic applications of the alpha antagonists, yohimbine, piperoxan, and phentolamine. In contrast, the beta antagonist, sotalol, and the alpha 1 antagonist, prazosin, were found ineffective when similarly applied. It is concluded that CAs and clonidine are inhibitory to the maintained activity of SPNs and that an alpha2-adrenergic receptor may be involved in the action of these compounds.

https://www.jneurosci.org/content/jneuro/1/8/908.full.pdf

JB Cabot

Papers

Inhibition of sympathetic preganglionic neurons by catecholamines and clonidine: mediation by an alpha-adrenergic receptor