9.1 INTRODUCTION
9.1.1
Adrenergic agonists in spinal analgesia
Previous chapters have discussed the pharmacology of opioids in the production of spinal antinociception. Interest in other spinal
neurotransmitter systems together with a desire to improve the management of pain, for instance when opioid-tolerance or opioid insensitivity is present, has led to the examination of the role of adrenergic mechanisms amongst others in spinal nociception.
The existence of a descending noradrenergic system originating in the brainstem which modulates noxious inputs in the spinal cord when activated by supraspinal electrical stimulation or opioid agonists is well established (see introduction). In addition behavioural antinociception is produced by the direct spinal administration of noradrenaline and other adrenergic agonists (Yaksh,1985) which also inhibit the nociceptive responses of convergent neurones after iontophoretic or intrathecal administration into the dorsal horn (Engberg and Ryall,1966; Belcher et al,1978; Headley et al,1978; Satoh et al, 1979; Collins et al,1984;
Willcockson et al, 1984; Davies and Quinlan, 1985; Fleetwood-Walker et al, 1985; Howe and Zieglansberger, 1987; Wilcox et al, 1987).
Both a and p adrenoceptors are found in the rat spinal cord (Young and Kuhar, 1980; Unnerstall et al, 1984) but binding sites for selective U2-
adrenoceptor ligands predominate in the superficial laminae of the dorsal horn where nociceptive afferents terminate (Young and Kuhar, 1980; Unnerstall et al, 1984). Furthermore following early behavioural studies indicating the involvement of a rather than p adrenoceptors in spinal antinociception (Kuraishi et al,1977; Reddy et al, 1980) antagonist studies suggested that the spinal antinociception produced by either activation of the endogenous descending noradrenergic pathway (Sagen and Proudfit,
1984; Barbaro et al, 1985; Camarata and Yaksh,1985; Jones and
Gebhart,1986) or spinal application of exogenous adrenergic agonists was mediated by the a2-adrenoceptor (Howe et al, 1983; Davies and
Quinlan, 1985; Fleetwood-Walker et al,1985). The present study sought to confirm the involvement of this receptor in depressing noxious-evoked dorsal horn neuronal responses in the rat, previously examined in
cat (Davies and Quinlan,1985; Fleetwood-Walker et al,1985)
9.1.2
Opioid-adrenergic interactions
Early studies reported the potentiation of systemic morphine by systemic clonidine (Spaulding et al,1979; Konno and Takayanagi,1984) an interaction proposed to be mediated by spinal a2 adrenoceptors (Ossipov
et al, 1984). The involvement of spinal a2-adrenoceptors in potentiating
the behavioural antinociceptive effects of intrathecal morphine has been reported in the primate (Yaksh and Reddy, 1981) and also in the rat (Wang et al, 1980) where intrathecal administration of the selective «2-
adrenergic agonist ST91 decreased the antinociceptive ED5Q for
morphine 7-fold. In mice subanalgesic doses of intrathecal NA
potentiated the antinociceptive activity of intrathecal morphine to SP- induced noxious stimuli (Hylden and Wilcox, 1983). Potentiation of analgesia by spinal clonidine in conjunction with spinal morphine has also been reported in humans (Tamsen and Gordh,1984; Coombs et al, 1985).
Prior to the present investigation electrophysiological evidence to support a role for a positive interaction between opioid and adrenergic spinal antinociception was scarce. In one study in cats intrathecal
adrenaline enhanced the suppression of convergent neuronal activity in the dorsal horn by morphine (Collins et al, 1984). The examination of drug effects in an electrophysiological model provides a necessary adjunct to behavioural evidence of antinociceptive effects. This is partieulary true with respect to adrenergic agonists which can have widespread
sympathomimetic actions which may interfere with behavioural nociceptive testing such as sedation after systemic administration
(Mahoney, 1990) or motor impairment after intrathecal administration (Reddy et el, 1980; Milne et al, 1985). Additionally changes in tail- temperature after intrathecal adrenergic agonists (LoPachin et al, 1984) can interfere with behavioural analgesic tests involving a noxious heat stimulus to this site (Berge et al, 1988). Thus the present study sought to investigate opioid/adrenergic spinal interactions in an electrophysiological model free of these disadvantages.
9.1.3
Selective a
2~adrenergic agonists and antagonists
Agonists with good selectivity for the « 2 adrenoceptor and alsoselective adrenergic antagonists were used in the present study to confirm the role of this receptor in the modulation of spinal nociception and
interaction with opioids. Clonidine is an established «2 adrenoceptor agonist and has been used extensively in antinociceptive studies. Also used was a newly developed agonist dexmedetomidine, the active enantiomer of the highly selective and potent a2 adrenergic agonist medetomidine
(Virtanen,1988; 1989).
Table 9.1: Selectivity o f a2 adrenergic agonists.
Ki ( a i ) Ki ((%2) a 2 / a i
Medetomidine 175 ± 567 1.08 ± 0.23 1620
Clonidine 713 ± 109 3.2 ± 1.18 220
(Ki values measured by displacement of pH]clonidine and prazosin in rat brain membranes; data from Virtanen,1988)
Medetomidine, used as a sedative/analgesic agent in veterinary practice, produces behavioural analgesia in some tests of nociception (acetic-acid writhing / formalin) (Virtanen,1989; Pertovaara et a l,1990). Although the sedatory effects of this agonist were thought to contribute to the positive results (Pertovaara et al, 1990) an electrophysiological study clearly showed inhibitions of nociceptive responses of spinothalamic neurones by medetomidine (Pertovaara et al, 1991). Recent behavioural studies report potent antinociception after spinal administration of dexmedetomidine, at sub-sedative doses (Fisher et al, 1991; Kalso et al, 1991) and this agonist also inhibited the slow ventral root potential in neonatal rat cord in vitro (Kendig et al,1991).
9.2 R E S U L T S
9.2.1
Clonidine and dexmedetomidine on dorsal horn
neuronal responses
Both clonidine and dexmedetomidine depressed C fibre responses in a dose-dependent manner (fig. 9.1). However whereas 100 pg clonidine only produced a maximal 60% inhibition of C fibre evoked responses 10 pg dexmedetomidine could inhibit responses completely. The
antinociceptive potency of dexmedetomidine in reducing C fibre-evoked responses to 50% of control (ED^Q=2.5pg; 11 nmol) was 17 times greater than clonidine (ED^Q=50pg; 190 nmol) and equivalent to the
antinociceptive potency of morphine and DSTBULET in this model , As with p opioid agonists facilitations were seen at the lower end of the dose-response curve for both agonists. Three out of 7 cells were excited after 0.5 pg clonidine (137 ± 10 % of control) and 3/4 cells after 0.5 pg dexmedetomidine (115 ± 1 % of control). A lower dose of
dexmedetomidine was inactive.
Ap responses could be considerably reduced by either agonists. In individual neurones the inhibition of the Ap response sometimes followed that of the C fibre response and was inhibited to the same degree.
However overall there was some degree of selectivity for inhibition of C fibre responses over Ap particulary at the upper end of the dose-response curves (fig. 9.1).
A. CLONIDINE