Pharmacological profiles of alpha 2 adrenergic receptor agonists identified using genetically altered mice and isobolographic analysis

Abstract

Endogenous, descending noradrenergic fibers convey powerful analgesic control over spinal afferent circuitry mediating the rostrad transmission of pain signals. These fibers target alpha 2 adrenergic receptors (α 2 ARs) on both primary afferent terminals and secondary neurons, and their activation mediates substantial inhibitory control over this transmission, rivaling that of opioid receptors which share similar a similar pattern of distribution. The terminals of primary afferent nociceptive neurons and secondary spinal dorsal horn neurons express α 2A AR and α 2C AR subtypes, respectively. Spinal delivery of these agents serves to reduce their side effects, which are mediated largely at supraspinal sites, by concentrating the drugs at the spinal level. Targeting these spinal α 2 ARs with one of five selective therapeutic agonists, clonidine, dexmedetomidine, brimonidine, ST91 and moxonidine, produces significant antinociception that can work in concert with opioid agonists to yield synergistic antinociception. Application of several genetically altered mouse lines had facilitated identification of the primary receptor subtypes that likely mediate the antinociceptive effects of these agents. This review provides first an anatomical description of the localization of the three subtypes in the central nervous system, second a detailed account of the pharmacological history of each of these six primary agonists, and finally a comprehensive report of the specific interactions of other GPCR agonists with each of the six principal α 2 AR agonists featured.

Effectiveness of dexmedetomidine for emergence agitation in infants undergoing palatoplasty: a randomized controlled trial

“…Dex demonstrates peripheral and centrally mediated antinociception via receptor activation in the dorsal horn and the locus coeruleus. 25,26 Dex administered before the end of surgery reduced morphine requirement in the immediate postoperative period in adult patients undergoing major abdominal or orthopedic procedures. 27 Patel et al 14 also reported that an intraoperative infusion of Dex significantly reduced the postoperative opioid requirement in children.…”

Modulation of α2-Adrenoceptor Functions by Heterotrimeric Gαi Protein Isoforms

“…Activation of ␣ 2A -receptors could be linked with bradycardia and hypotension (MacMillan et al, 1996), sedation (Lakhlani et al, 1997;Gilsbach et al, 2009), and consolidation of working memory (Wang et al, 2007). Hypothermia and antinociception induced by ␣ 2 -agonists depend primarily on functional ␣ 2A -adrenoceptors (Stone et al, 1997;Gilsbach et al, 2009), but other subtypes may also contribute to these pharmacological effects under certain conditions (Sallinen et al, 1997;Fairbanks et al, 2009). …”

Role of Intravenous Dexmedetomidine in Prolonging Postoperative Analgesia and Quality of Block Following Spinal Anaesthesia. A Systemic Review and Update

“…Brain and spinal alpha 2 receptor activation inhibit neuronal firing, which leads to hypo tension, bradycardia, sedation and analgesia. Apart from action in nervous system, extraneuronal alpha 2 activation leads to decrease in salivation and secretions, decrease gastric motility, inhibit renin release, increased glomerular filtration rate; decreased intraocular pressure and decrease insulin secretion from the pancreas [18,19]. There are various sub classification of alpha 2 receptor, alpha 2 A, B and C [16].…”

“…Apart from prolonging analgesia, it has been used for prevention and treatment of shivering [14][15][16][17][18][19][20][21][22][23].…”