Adrenergic and Cholinergic Compounds

16 May

R. D. Sanders • M. Maze (✉)
Academic Anaesthetics, Imperial College, Chelsea and Westminster Hospital, 369 Fulham
Road, London SW10 9NH, UK
m.maze@ic.ac.uk

References

Abstract Adrenergic and cholinergic signalling contributes significantly to the endogenous antinociceptive system. Exogenous α2 adrenergic agonists have a well-established analgesic profile; however, recent investigations suggest that this class of agents is underused,  and herein we highlight the potential for both current  application and future development of these agents. Nicotinic and muscarinic cholinergic ligands represent a novel class of agents with much promise for the management  of problematic  pain. In this chapter  we review

advances in both preclinical and clinical arenas and highlight potential avenues for further research.

Keywords  Pain · Antinociception  · Adrenergic · Clonidine · Dexmedetomidine  · Cholinergic · Nicotinic · Muscarinic

Introduction

Pain management  remains a real and current  problem in clinical medicine; in the United States 70%–80% of surgical patients experience moderate to se- vere post-operative pain (Owen et al. 1990; Svensson et al. 2000; Thomas et al.

1998). This does not merely reflect inadequate pain management strategies at a local level but also poor efficacy and poor tolerability of the analgesic agents.

For example, opioid administration is commonly limited by side-effects from respiratory  and gastrointestinal  symptoms. To enable more effective therapy multi-modal strategies are now employed; however, new agents with improved

efficacy are required  to help combat problematic  pain management.  In ad- dition, chronic and neuropathic  pain syndromes remain resistant to current approaches, with only a minority of patients responding mostly at the expense

of significant side-effects (Arner and Meyerson 1988).

With administration via systemic or regional approaches for acute, chronic and neuropathic  pain, α2 adrenergic agonists remain a potent but relatively underused class of analgesic agents. Below we review supporting evidence for an expanding role of this class of agents and explore their mechanisms of action.

At present, cholinergic compounds, both nicotinic and muscarinic, are being developed as novel analgesics and herein we review their progress. Further- more, there is substantial overlap in the mechanisms of action of both of these classes of agents; further scientific exploration is required to inform us about their potential adjuvant administration.

Adrenergic Compounds

Adrenergic signalling is one of the primary components  of the endogenous antinociceptive  system that modulates  pain responses. Acting at spinal and supraspinal  sites, norepinephrine release is involved in the control of a wide

range of pain responses via activation of α2 and α1 adrenoceptors. Descending inhibitory neurons (DINs) are an important component of the antinociceptive system. Activated from supraspinal sites such as the periaqueductal  grey and

dorsal raphe nucleus (Jones and Gebhart 1984; Tjolsen et al. 1990) as well as other brainstem  nuclei such as the A5 and A7, they inhibit  the nociceptive responses in the dorsal horn of the spinal cord via release of norepinephrine,

serotonin  and acetylcholine (Li and Zhuo 2001). In the dorsal horn,  nore- pinephrine  depresses wide-dynamic-range  neuron  responses after Aδ and C nociceptive fibre activation  by stimulation  of α2  adrenoceptors  (Jones and Gebhart 1984). This effect of norepinephrine is mimicked by exogenous α2 adrenoceptor  agonists (Millar et al. 1993) and is thought to be dependent  on

stimulation  of spontaneously  active neurons  in the deep layer of the spinal

cord which release acetylcholine and enkephalins. Further indirect evidence is provided by the observation that acute pain increases norepinephrine and acetylcholine levels in the cerebrospinal fluid (CSF), and the α2 adrenoceptor agonist clonidine increases acetylcholine in the CSF (Eisenach et al. 1996; De- tweiler et al. 1993). This also indicates an interdependent antinociceptive effect

exerted between the cholinergic and adrenergic systems.

α2 Adrenergic Receptors and Substrates

When stimulated, α2 adrenoceptors  inhibit adenyl cyclase via pertussis-sen- sitive G proteins. These receptors are coupled, via the subunits of the G protein, to ligand-gated ion channels including the N-type calcium channel (inhibition; Adamson et al. 1989), the P/Q-type calcium channel (inhibition; Ishibashi et al.

1995), the IA potassium  channel (activation; North et al. 1987), the calcium activated potassium channel (activation; Ryan et al. 1998), the ATP-sensitive potassium  channel  (activation;  Galeotti et al. 1999), the voltage-dependent potassium  channels (activation; Galeotti et al. 1999) and the Na+/H+  anti- porter (activation; Ryan et al. 1998). Furthermore, recent work has highlighted

the association of α2 adrenoceptors with G protein-coupled inwardly rectifying potassium (GIRK) channels (Blednov et al. 2003; Mitrovic et al. 2003).

Pharmacogenetic Studies

Using D79N mice which express dysfunctional α2A adrenoceptors,  Lakhlani and colleagues showed that adrenoceptor agonist antinociception  (assessed by the hot  plate test)  and  sedation  were dependent  on this receptor  sub- type (Lakhlani et al. 1997). In the absence of functional α2A adrenoceptors, the agents could not suppress  voltage-gated calcium or activate potassium currents.  This mutation  did  not  affect morphine  analgesia. It is notewor-

thy, though, that pharmacogenetic  analysis of different inbred mouse strains showed significant correlation  between strain dependence  of morphine  and clonidine analgesia (in hot plate and formalin tests; Wilson et al. 2003). Fur- thermore,  as the interaction  between clonidine and morphine  is synergistic (Wilcox et al. 1987) and there are overlapping pharmacogenomic  substrates, investigation  of downstream  effectors beyond the receptor  may lead to the development of novel agents which separate analgesic and sedative effects of

α2 adrenoceptor  agonists.

Site of Action

Supraspinal and spinal targets contribute to the potent antinociceptive efficacy of α2 adrenoceptor  agonists. This is of importance  because drugs which rely

on DINs such as nitrous oxide are ineffective in the young, as DINs are imma- ture in early development (Ohashi et al. 2002). The α2A adrenoceptor  agonist dexmedetomidine  (Dex) is effective in the immature  phenotype as it targets both supraspinal and spinal sites, circumventing DINs (Sanders et al. 2005).

Supraspinal Effects

The locus coeruleus (LC) is an adrenergic centre in the brainstem that tonically inhibits  the A5 and A7, which are then  coupled to DINs. Activation of α2 adrenoceptors in the LC inhibits neuronal firing in this region (Guo et al. 1996). Inhibition  of the LC by discrete administration of α2 adrenoceptor  agonists leads to ‘disinhibition’ (i.e. activation) of the A5 and A7 and therefore DINs.

Spinal Effects

Comparison  between the analgesic effectiveness of clonidine after systemic or neuraxial (spinal or epidural) administration revealed that the spinal cord was an important site of action for α2 adrenoceptor agonist-induced analgesia (Bernard  et al. 1995; Eisenach et al. 1998). Furthermore,  in human  volun-

teers intrathecal (IT) clonidine was superior to intravenous  clonidine against capsaicin and thermal pain (Eisenach et al. 1998).

In the dorsal horn of the spinal cord, activation of pre-synaptic α2 adreno- ceptors reduces glutamate (Li and Eisenach 2001), substance P and calcitonin

gene-related peptide (CGRP) release (Takano and Yaksh 1993). Post-synaptic effects are related to activation of voltage-dependent potassium channels (Ga- leotti et al. 1999) and GIRK channels (Blednov et al. 2003; Mitrovic et al. 2003).

In two separate studies the action of clonidine was examined in GIRK-2-null mutant mice using the hot plate test and tail flick latency (Blednov et al. 2003; Mitrovic et al. 2003); the mutation reduced clonidine antinociception almost to baseline, indicating primarily a post-synaptic action of clonidine. We have pre-

viously found electrophysiological evidence to support  this genetic evidence of a post-synaptic action for α2 adrenoceptor  agonists as Dex reduces ventral root potentials  (induced by substance P) in an ex vivo isolated neonatal rat spinal cord preparation. In addition, α2 adrenoceptor  agonists inhibit adenyl cyclase, which is a pivotal enzymatic step in the development of hyperalgesia at post-synaptic sites (Hoeger-Bement and Sluka 2003; Sanders et al. 2005).

Systemic administration of α2 adrenoceptor  agonists induces antinocicep- tion in several animal models with effects both at supraspinal and spinal sites. Both clonidine and dexmedetomidine  increase latency of tail flick during the hot plate test in a dose-related manner (Sabbe et al. 1994). Formalin and cap-

saicin induce inflammatory  pain with a typical biphasic pain response (acute pain and secondary hyperalgesia). α2 Adrenoceptor agonists inhibit this pain

response (Wilson et al. 2003; Sanders et al. 2005) likely via both pre-synaptic (reduction of glutamate, substance P and CGRP release) and post-synaptic (ac- tivation of GIRK channels and inhibition of adenyl cyclase) mechanisms. This

underlies the known efficacy of α2 adrenoceptor  agonists in hyperalgesia and neuropathic  pain-associated  allodynia; α2  adrenoceptor  agonists may even show increased efficacy against neuropathic pain (Puke and Wiesenfeld-Hallin

1993). Furthermore, α2 adrenoceptor agonists reduce allodynia after nerve le- sioning models of neuropathic pain (Poree et al. 1998), which may be related to peripheral  adrenoceptor  activation. This potent anti-neuropathic pain effect is also reduced by acetylcholine depletion in the spinal cord (Paqueron et al.

2001) and muscarinic cholinergic antagonists  (Pan et al. 1999) likely via M4 receptors (Kang and Eisenach 2003). The α2 adrenoceptor  agonists also show efficacy against visceral pain (Harada et al. 1995; Iwasaki et al. 1991) and at peripheral—such  as intra-articular injection—sites (potentially mediated by

local enkephalin release; Nakamura and Ferreira 1988).

Likewise, α2 adrenoceptor agonists have long been administered for regional anaesthesia; after spinal administration in sheep they interact synergistically

with opioid and cholinergic agonists and cholinesterase  inhibitors  such as neostigmine  (Detweiler et al. 1993). This synergistic interaction  has yet to be observed in humans, but opioid analgesia is enhanced in the presence of

clonidine (at doses of up to 75 μg IT; Grace et al. 1994). Similarly, combination of spinal neostigmine and clonidine prolongs post-operative  analgesia (Pan et al. 1998). Therefore, whether administered  systemically or neuraxially, α2

adrenoceptor  agonists exert their primary analgesic effect at the level of the spinal cord.

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