The Contribution of Alpha-1 and Alpha-2 Adrenoceptors
in Peripheral Imidazoline and Adrenoceptor
Agonist-Induced Nociception
Ahmet Dogrul, MD
I
˙
lke Coskun
Tayfun Uzbay
We evaluated the effects of activation of peripheral adrenoceptors (AR) and
imidazoline receptors on nociception and the contribution of -1 and -2 AR
receptors in agonist-induced nociception by using the tail-flick test in mice.
Clonidine (-2 AR agonist), agmatine (imidazoline receptor and -2 AR agonist),
noradrenaline (mixed -1 and -2 AR agonist), phenylephrine (-1 AR agonist), or
0.9% saline was given by intradermal injection (10 L) into the tail. The intradermal
injection of clonidine (1, 3, and 10 g) and agmatine (3, 30, and 50 g) produced
dose-dependent antinociception, whereas noradrenaline (1, 10, and 30 g) and
phenylephrine (1, 10 and 30 g) produced dose-dependent thermal hyperalgesia.
Clonidine (10 g) and agmatine (50 g)-induced peripheral antinociception were
antagonized by pretreatment with yohimbine (2.5 mg/kg IP), a selective -2 AR
antagonist, but not by prazosin (1 mg/kg IP), a selective -1 AR antagonist.
Noradrenaline (30 g) and phenylephrine (30 g)-induced thermal hyperalgesia
were antagonized by prazosin (1 mg/kg IP) but not by yohimbine (2.5 mg/kg IP).
Our results suggest that local thermal hyperalgesic effects of noradrenaline and
phenylephrine are linked to -1 AR and the peripheral antinociceptive action of
clonidine and agmatine are linked to -2 AR.
(Anesth Analg 2006;103:471–7)
Noradrenaline (NE), a principal neurotransmitter
in the sympathetic nervous system, is involved in
various body functions, including nociception (1–3).
NE is the endogenous ligand for both - and
-adrenergic receptor (AR). It is generally accepted
that the AR plays an important role in the modula-
tion of nociception by the sympathetic nervous system
(2). However, there is some controversy regarding the
roles of each of the AR subtypes, -1 and -2, in
nociception (2– 4). The spinal administration of NE, a
mixed -1 and -2 AR agonist, or of phenylephrine, an
-1 receptor agonist, has been reported to produce
antinociception (3,5). However, other studies showed
that intradermal injection of NE and phenylephrine
produced pain and hyperalgesia (6,7). Thus, NE and
phenylephrine can be either pronociceptive or antino-
ciceptive, depending on the site of delivery. On the
other hand, either spinal or topical administration of
clonidine, an -2 AR agonist, produced antinocicep-
tion (8). However, there is evidence that several phar-
macologic actions of -2 AR agonists are mediated via
activation of not only -2 AR but also by imidazoline
receptors (3). Agmatine has recently been found in
various tissues and in the central nervous system,
where it represents a novel neurotransmitter/
neuromodulator (10,11). Many studies have shown
that agmatine binds to both the imidazoline receptors
and to the 2-AR (3,9,10).
After systemic administration, drugs can be distrib-
uted in peripheral, spinal, and supraspinal sites. The
relative contribution of these different sites to the
overall pharmacologic effect of a receptor agonist
depends on several factors, such as the location of the
relevant receptors, the site of administration (sys-
temic, local-peripheral, or spinal), and redistribution
from the site of drug administration. The neuronal
pathways and architecture within spinal and su-
praspinal sites are very complex, making it difficult to
elucidate the role of individual subtypes of
-adrenergic receptors in the modulation of nocicep-
tion. The skin is innervated with sensory nerve termi-
nals and has cutaneous nociceptors responsive to heat
in the superficial layers of the epidermis (11). Sympa-
thetic postganglionic efferents are involved in the
modulation of nociceptive transmission in the periph-
ery (2). The localized peripheral administration of
drugs allows a larger local concentration of drug at the
site of injection, while leading to a smaller systemic
From the Gu ¨ lhane Military Medical Academy, Faculty of Medi-
cine, Department of Medical Pharmacology, Psychopharmacology
Research Unit, Ankara, Turkey.
Accepted for publication April 10, 2006.
Address correspondence and reprint requests to Ahmet Dogrul,
MD, Gu ¨ lhane Military Medical Academy, Faculty of Medicine,
Department of Medical Pharmacology, Ankara, Turkey. Address
e-mail to dogrula@gata.edu.tr.
Copyright © 2006 International Anesthesia Research Society
DOI: 10.1213/01.ane.0000223680.54063.f6
Vol. 103, No. 2, August 2006 471