Descending control of pain

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Abstract

Upon receipt in the dorsal horn (DH) of the spinal cord, nociceptive (pain-signalling) information from the viscera, skin and other organs is subject to extensive processing by a diversity of mechanisms, certain of which enhance, and certain of which inhibit, its transfer to higher centres. In this regard, a network of descending pathways projecting from cerebral structures to the DH plays a complex and crucial role. Specific centrifugal pathways either suppress (descending inhibition) or potentiate (descending facilitation) passage of nociceptive messages to the brain. Engagement of descending inhibition by the opioid analgesic, morphine, fulfils an important role in its pain-relieving properties, while induction of analgesia by the adrenergic agonist, clonidine, reflects actions at α2-adrenoceptors (α2-ARs) in the DH normally recruited by descending pathways. However, opioids and adrenergic agents exploit but a tiny fraction of the vast panoply of mechanisms now known to be involved in the induction and/or expression of descending controls. For example, no drug interfering with descending facilitation is currently available for clinical use. The present review focuses on: (1) the organisation of descending pathways and their pathophysiological significance; (2) the role of individual transmitters and specific receptor types in the modulation and expression of mechanisms of descending inhibition and facilitation and (3) the advantages and limitations of established and innovative analgesic strategies which act by manipulation of descending controls. Knowledge of descending pathways has increased exponentially in recent years, so this is an opportune moment to survey their operation and therapeutic relevance to the improved management of pain.

Section snippets

General introduction: scope and aims of review

Some 30-odd years ago, the concept was evoked that nociceptive information impinging upon the dorsal horn (DH) of the spinal cord from the skin, viscera and other tissues, is not automatically transferred to higher centres (Melzack and Wall, 1965). Rather, in accordance with now familiar “gate” terminology, processes integrated at the terminals of nocisponsive (pain-sensitive) primary afferent fibres (PAFs), and at the projection neurones (PNs) which they target, profoundly modify nociceptive

Neuronal circuitry in the DH

For an understanding of the operation of descending pathways, it is essential to briefly consider their relationship to PAFs and other neuronal elements in the DH (Fig. 1). There is a vast literature devoted to synaptic processing of nociceptive input in the DH and the reader is referred to several more thorough and technical accounts for additional information Besson and Chaouch, 1987, Willis, 1988, Willis and Coggeshall, 1991, Levine et al., 1993, Todd and Spike, 1993, Coggeshall and Carlton,

Common sites of origin for mechanisms of descending inhibition and facilitation

There is no absolute anatomical separation between structures involved in the initiation of mechanisms of DI as compared to DF (Table 1). Common loci in both the rostroventromedial medulla (RVM) and NTS, for example, give rise to descending pathways engendering DI or DF, albeit via contrasting mechanisms. Fields et al., 1991, Watkins et al., 1994, Wiertelak et al., 1997, Fields and Basbaum, 1999, McNally, 1999, Urban et al., 1999a, Urban et al., 1999b, Urban et al., 1999c, Nuseir and Proudfit,

Interplay of descending inhibition and facilitation in the signalling of nociceptive information

In general, for pain reflecting excessive stimulation of specialised nociceptors, there is an adaptive relationship between the signalling of noxious stimuli and actual or impending tissue damage, corresponding to the crucial warning function of pain. However, the “input–output” equation for nociceptive transmission is far from invariant and may be weighted either in favour of, or against, its passage by an abundance of mechanisms including DI and DF Besson and Chaouch, 1987, Willis and

Multiple classes of adrenoceptor

Three major classes of AR can be recognised: α1-, α2- and β-ARs Ruffolo et al., 1993, Bylund et al., 1994, Hieble et al., 1995, Kukkonen et al., 2001, Piascik and Perez, 2001. Three subtypes of the former have been cloned: α1A, α1B and α1D, which are collectively characterised by their positive coupling via Gq/11 to voltage-gated Ca2+-channels and phospholipase C (PLC), activation of which mobilises intracellular pools of calcium. (The pharmacologically-defined α1C-AR has been abandoned)

Multiple classes of dopamine receptor

Dopamine (DA) receptors are classified into two families: D2-like, incorporating D2 and closely-related D3 and D4 receptors, and D1-like which includes D1 and closely-related D5 receptors Missale et al., 1998, Vallone et al., 2000. Stimulation of D2, D3 and D4 receptors leads, via Gi/o, to the inhibition of AC. Activation of D2 receptors also suppresses and potentiates Ca2+- and K+-currents, respectively, although such actions have proven difficult to detect for their D3 and D4 counterparts.

Origins and projection patterns to the DH

Although a small population of 5-HT-immunoreactive cell bodies has been identified ventral to the central canal in primates (LaMotte, 1988), virtually the entire serotonergic innervation of the spinal cord in these and other species is derived from supraspinal sources. In this regard, a modest proportion of serotonergic neurones from the dorsal raphe nucleus—which predominantly innervates the thalamus, dorsal hippocampus, striatum, cerebral cortex-sends collaterals to the spinal cord and the

Multiple receptors and origins of descending histaminergic pathways

Histamine exerts its actions via four classes of receptor. Of these, H1, H2 and H3 receptors are found in the CNS, and the latter functions both post-synaptically to histaminergic neurones and as an autoreceptor on their terminals Hough, 1988, Hough, 2001. Both H1 receptors (which couple positively to PLC and PhospolipaseA2) as well as H2 receptors (which couple positively to AC) are excitatory. H3 receptors (which are negatively coupled to AC and Ca2+-currents) are inhibitory, in line with

Multiple receptors and origins of cholinergic neurones in the dorsal horn

Cholinergic mechanisms for the modulation of nociception are particularly intriguing (Table 2) inasmuch as ACh may be involved: (1) in the activation of non-cholinergic descending pathways mediating DI; (2) in the mediation of DI following its own release from descending pathways and (3) in the induction of antinociception following release from ININs in the DH. Further, ACh modulates nociception by a complex pattern of effects mediated via multiple classes of muscarinic and nicotinic receptor

Substance P

A familiar feature of the DH is the massive provision of SP (and neurokinin (NK) A)-containing, fine calibre PAFs to superficial laminae of the DH which, via activation of NK1- and, possibly, NK2- and NK3-receptors play an important role in nociceptive transmission Cao et al., 1995, Seguin et al., 1995, Mantyh et al., 1995, DeFelipe et al., 1998, Millan, 1999, Yaksh, 1999a, Laird et al., 2000, Martinez-Caro and Laird, 2000, Ribeiro-da-silva and Hökfelt, 2000, Kamp et al., 2001, Todd et al., 2000

Generation of cannabinoids: actions at CB1 receptors

Of the two classes of cannabinoid receptor to date characterized, CB1 and CB2, only the former appears to be localized in the CNS (Pertwee, 1997). Although there is increasing evidence for promiscuous (pleiotropic) coupling of CB1 receptors via various classes of G-protein to intracellular transduction mechanisms Pertwee, 1997, Pertwee, 2001, Abadji et al., 1999, Ameri, 1999 they are well-established to negatively couple via Gi/o to AC and to enhance and suppress K+- and Ca2+-currents,

General considerations

In the therapeutic exploitation of descending controls for improved pain relief, the ultimate objective would be to develop an orally-active formulation of a drug with the following characteristics: (1) effective in all patients against inflammatory and/or neuropathic pain of disparate pathologies; (2) active over a well-defined dose-range; (3) selectively suppressing nociceptive as compared to non-nociceptive input; (4) with an appropriate duration of action; (5) devoid of problems of

General discussion

In concluding the present review, it is instructive to recall several major themes which are likely to inform future research into the physiological significance and therapeutic relevance of descending controls of nociceptive processing.

First, it is critical to establish patterns of neuronal connections both in the DH and in structures from which descending controls originate, in particular as regards the transmitters and multiple classes of receptor via which individual classes of neurone

Concluding comments

The proliferation of potential analgesic drug targets for the therapeutic manipulation of descending controls is testimony to the intensive and highly-successful research programme of the past decades. In parallel, great efforts have been invested in the characterization of peripheral and central mechanisms involved in the induction of nociception. Further, there is an increasing awareness of the importance of the cognitive–affective component of pain (appreciation, tolerance and coping).

Acknowledgments

The author would like to thank M. Soubeyran, J.-M. Rivet, A. Gobert, A. Dekeyne, M. Brocco, S. Dapremont and D. Passerieux for invaluable assistance in the preparation of this article, together with J.-M. Besson, A. Dickenson and M. Hamon for helpful comments on the manuscript.

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