Pharmacological Properties, Central Nervous System Effects, and Potential Therapeutic Applications of Atipamezole, a Selective α₂‐Adrenoceptor Antagonist

Abstract

Atipamezole is an alpha2-adrenoceptor antagonist with an imidazole structure. Receptor binding studies indicate that its affinity for alpha2-adrenoceptors and its alpha2/alpha1 selectivity ratio are considerably higher than those of yohimbine, the prototype alpha2-adrenoceptor antagonist. Atipamezole is not selective for subtypes of alpha2-adrenoceptors. Unlike many other alpha2-adrenoceptor antagonists, it has negligible affinity for 5-HT1A and I2 binding sites. Atipamezole is rapidly absorbed and distributed from the periphery to the central nervous system. In humans, atipamezole at doses up to 30 mg/subject produced no cardiovascular or subjective side effects, while at a high dose (100 mg/subject) it produced subjective symptoms, such as motor restlessness, and an increase in blood pressure. Atipamezole rapidly reverses sedation/anesthesia induced by alpha2-adrenoceptor agonists. Due to this property, atipamezole is commonly used by veterinarians to awaken animals from sedation/anesthesia induced by alpha2-adrenoceptor agonists alone or in combination with various anesthetics. Atipamezole increased sexual activity in rats and monkeys. In animals with sustained nociception, atipamezole increased pain-related responses by blocking the noradrenergic feedback inhibition of pain. In tests assessing cognitive functions, atipamezole at low doses has beneficial effects on alertness, selective attention, planning, learning, and recall in experimental animals, but not necessarily on short-term working memory. At higher doses atipamezole impaired performance in tests of cognitive functions, probably due to noradrenergic overactivity. Recent experimental animal studies suggest that atipamezole might have beneficial effects in the recovery from brain damage and might potentiate the anti-Parkinsonian effects of dopaminergic drugs. In phase I studies atipamezole has been well tolerated by human subjects.

Optoactivation of Locus Ceruleus Neurons Evokes Bidirectional Changes in Thermal Nociception in Rats

“…It is a relatively small structure with ϳ3000 neurons in the rat (Loughlin et al, 1986a) and, although these cells are considered homogenous with respect to their NAergic neurochemistry, they can be divided into several different subgroups based on cell morphology and efferent targets (Loughlin et al, 1986b;Berridge and Waterhouse, 2003;Aston-Jones, 2004). With respect to pain control, it is the descending projections to the spinal dorsal horn that have received the most attention (Jones, 1991;Millan, 2002;Pertovaara, 2006) and these are predominantly located in the ventral pole and in the subceruleus (Westlund et al, 1983;Howorth et al, 2009a;Bruinstroop et al, 2012). Previous studies have shown that focal stimulation (electrical and/or chemical) of the LC region can produce antinociceptive effects (Margalit and Segal, 1979;Jones and Gebhart, 1986b;Jones, 1991;West et al, 1993).…”

“…The LC is proposed to play an important role in an endogenous descending pain control circuit (Jones, 1991;Millan, 2002;Pertovaara, 2006). Given that this NAergic circuit component appears to be functionally underactive in chronic neuropathic pain (Howorth et al, 2009b;Alba-Delgado et al, 2012;Hughes et al, 2013), we have been interested in exploring the nature of this deficit and developing strategies to augment its activity.…”

“…Despite this knowledge of the analgesic potential of the pontospinal NAergic system; the use of systemic ␣2-adrenergic agonists to mimic its action in the treatment of pain is limited by a confounding side effect profile including sedation and hypotension (Pertovaara, 2006). The sedation can be reduced by longterm intrathecal infusion (Hassenbusch et al, 2002), but this is reserved for the most severe patients because it is expensive to deploy and can be associated with complications.…”

“…Since the original report that electrical stimulation of the midbrain produces profound analgesia (Reynolds, 1969), much attention has been focused on descending control systems, which can influence the spinal transmission of noxious inputs (Millan, 2002;Fields, 2004). The noradrenaline (NA)-containing neurons of the locus ceruleus (LC) and the A5 and A7 cell groups in the pons have been implicated as key components of this descending control system (Jones, 1991;Pertovaara, 2006).…”

Tissue Residue Levels of Butorphanol, Azaperone, Medetomidine, Atipamezole, and Naltrexone in White-tailed Deer (Odocoileus virginanus) at 11 and 21 Days Post Intramuscular Injection

“…These anesthetics and reversing drugs are labeled for use in traditional livestock, but in most of the situations with wildlife the same drugs are legally used in off-label procedures. Dosages, clearance times, and tissue residue levels for some of the above drugs have been established for some domesticated species [1][2][3][4], however, tissue residues have not been established for these drugs when used in white-tailed deer (Odocoileus virginianus). The levels of drug residues in the tissues of game animals like deer and elk that might be consumed by the public after the drug injection could be of some possible public health concern.…”