Ž.
European Journal of Pharmacology 378 1999 161–168
www.elsevier.nlrlocaterejphar
Do a -adrenoceptors play an integral role in the antinociceptive
2
mechanism of action of antidepressant compounds?
Alex M. Gray
1
, David M. Pache, Robert D.E. Sewell
)
Department of Pharmacology, The Welsh School of Pharmacy, Cardiff UniÕersity, King Edward VII AÕenue, Cathays Park, Cardiff CF10 3XF, Wales, UK
Received 14 June 1999; accepted 25 June 1999
Abstract
Antidepressants are analgesic in the absence or presence of depression. The underlying mechanisms probably involve a complex
interplay between several neurotransmitter systems and neuroreceptors. a-Adrenoceptors play an important role in pain processing and
a -adrenoceptor agonists have been used in clinical pain management so we have investigated whether a-adrenoceptor sub-types mediate
2
the antinociceptive activity of antidepressants. Thus, the abdominal constriction assay in mice was used to examine the antinociceptive
responses of a diverse range of antidepressants following a -ora -adrenoceptor antagonism. The antidepressants or monoamine
12
reuptake inhibitors included the serotonin selective reuptake inhibitor paroxetine, the serotonin–noradrenaline reuptake inhibitor
Ž. Ž.
sibutramine, the resolved q - and y -enantiomers of the noradrenaline reuptake inhibitor oxaprotiline, plus the tricyclics amitriptyline
and dothiepin. All these compounds have been previously shown to be antinociceptive in this paradigm. The respective a - and
1
Žw Ž.x.
a -adrenoceptor antagonists prazosin and RX821002 2- 2-methoxy-1,-4-benzodioxan-2-yl -2-imidazoline did not produce antinocicep-
2
tion though at 1.0 mg kg
y
1
; s.c., RX821002 but not prazosin blocked clonidine antinociception. The antinociceptive activity produced by
Ž. Ž.
sub-maximal doses of amitriptyline, dothiepin, sibutramine, paroxetine, q - and y -oxaprotiline were all blocked by RX821002 but not
by prazosin. Additionally, both morphine and aspirin antinociception was resistant to a - and a -adrenoceptor antagonism. Thus, a -
12 2
rather than a -adrenoceptors may play an integral role in antidepressant antinociception irrespective of the propensity for inhibiting
1
reuptake of not only noradrenaline but also serotonin. It is probable, however, that other differing pharmacological properties of some
antidepressants, such as opioid-like activity, may complicate any empirical correlation between monoamine uptake and analgesia. q 1999
Elsevier Science B.V. All rights reserved.
Keywords: Antidepressant; a -Adrenoceptor; Antinociception; Analgesia; Amitriptyline; Dothiepin; Paroxetine; Oxaprotiline enantiomer; Sibutramine
2
1. Introduction
Pain is often accompanied by depression, the incidence
of which ranges from 10% upwards to 100% in chronic
Ž.
pain patients Pilowsky et al., 1977; Turkington, 1980 .
Consequently, in the clinical literature, antidepressant ther-
apy has been advocated in the management of some pain
Ž
conditions both in the absence Gomersall and Stuart,
.Ž
1978 and presence Ward et al., 1979; Feinmann and
.
Harris, 1984; Max et al., 1987 of concomitant depression.
There has been considerable discussion at the experi-
mental level about the nature and underlying mechanisms
Ž
of antidepressant analgesia Biegon and Samuel, 1979,
)
Corresponding author. Tel.: q44-1222-874000; fax: q44-1222-
874149; E-mail: sewell@cardiff.ac.uk
1
Present address: PPD Pharmaco, 4025 Paramount Parkway, Mor-
risville, NC 27560, USA.
¨
1980; Ogren and Holm, 1980; Botney and Fields, 1983;
¨
.
Tura and Tura, 1990 . In the light of this debate, we have
recently shown that there is an involvement of opioidergic
systems in the dose-dependent analgesic profiles induced
by several types of antidepressant in laboratory studies
Ž.
Gray et al., 1998 . There are, however, other modulatory
neurotransmitter systems implicated in pain processes. A
classic example of this is provided by noradrenergic neu-
ronal pathways, where at least four major separate systems
Ž
are thought to modulate nociception Proudfit, 1988:
.
Sewell, 1991 . In this context, we have demonstrated that
agonists at a -adrenoceptors produce graded analgesia
2
with varying degrees of opioid-, 5-hydroxytrytamine-
Ž.
serotonin- or 5-HT- and a-adrenoceptor involvement
Ž.
Dobson et al., 1997 .
It is clear that central a -adrenoceptors play an impor-
2
tant role in pain processing. Indeed, a -adrenoceptor ago-
2
nists have been employed clinically in the management of
0014-2999r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.
Ž.
PII: S0014-2999 99 0 04 64-1