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INVITED REVIEW
School of Biomedical Sciences, Faculty of Health and Hunter Medical Research Institute, The University of Newcastle, Callaghan, New South Wales, Australia
Submitted 23 May 2007; accepted in final form 13 June 2007
ABSTRACT
Neurons in the superficial dorsal horn (SDH) of the spinal cord play a critical role in processing potentially painful or noxious signals from skin, muscle, and viscera. Many acute pain therapies are based on the notion that altering the excitability of SDH neurons can block or gate these signals and reduce pain. This same notion also underlies treatments for certain chronic pain states. Basic scientists are now beginning to identify a number of potential molecular targets for spinal cord–based pain therapies with a focus on ion channels and receptors that can alter neuronal excitability. The current challenge in pain research is to identify which are the most promising targets and how their manipulation alters pain processing. In this review, we propose that our understanding of spinal pain processing mechanisms and translation of these discoveries into pain therapies could be improved by 1) better appreciating and understanding neuronal heterogeneity in the SDH; 2) establishing connectivity patterns among SDH neuron types; and 3) testing and extending findings made in vitro to intact (in vivo) animal models. As this information becomes available, it will be possible to determine the precise distribution of potential therapeutic targets on various SDH neuron types within specific circuits known to be functionally important in spinal pain processing.
INTRODUCTION
The exact details of how the CNS processes noxious stimuli under normal and pathological conditions into a pain percept are complex and still poorly understood (Craig 2003b
; Millan 1999; Willis and Coggeshall 2004). The classic ascending pain-processing pathway is characterized by collections of neurons located in anatomically discrete locations, or processing nodes, along the neuroaxis. These nodes include regions like the spinal cord dorsal horn, midline brain stem centers, and the thalamus. The aim of current pain therapies is to alter neuronal excitability and thus ultimately affect signal processing at various nodes in this pathway (Fields and Basbaum 1999; Gebhart 2004; Mason 2005; Sandkuhler 1996). Therefore efforts have focused on examining how neurotransmitters, receptors, and ion channels can alter the excitability of neurons located in processing nodes. Because the superficial dorsal horn (SDH; laminae I-II) is the first central node in the pain pathway, it has received considerable attention, both as a site for understanding pain processing mechanisms and subsequent development of pain therapies.
The SDH is the major spinal target for small diameter (A
and C-fiber) primary afferents carrying noxious, thermal, itch, and innocuous tactile information (Christensen and Perl 1970; Sugiura et al. 1986; Tuckett and Wei 1987a,b; Vallbo et al. 1999). Evidence suggests that each of these modalities ascends the neuroaxis in relatively discrete parallel pathways (Green 2004; Ikoma et al. 2006; Patapoutian et al. 2003; Wallengren 2005); however, there is also potential for interaction and information exchange between modalities in the SDH. This review focuses on nociceptive processing; however, the views we express are also likely to be relevant for our understanding of temperature, itch, and tactile processing mechanisms in the SDH.
Figure 1 shows that nociceptive peripheral inputs make monosynaptic connections with projection neurons in lamina I and interneurons in laminae I and II (Light and Perl 1979; Light et al. 1979). Projection neurons in lamina I transmit nociceptive information out of the SDH to brain stem centers and the thalamus. Finally, information is relayed to cortical centers where the discriminative and affective components of pain are established (Craig 2003a,b; Ohara et al. 2005). At the level of the spinal cord, this view is convenient but simplistic and overlooks the fact that most SDH neurons (certainly >95%) are local circuit interneurons and not projection neurons (Polgar et al. 2004; Spike et al. 2003; Willis and Coggeshall 2004). These interneurons can be excitatory or inhibitory and receive inputs from higher brain centers and other local interneurons in addition to those from the periphery. Therefore it is acknowledged that these interneurons play a crucial role in setting the overall "excitability level" and hence output of the SDH (Willis and Coggeshall 2004).
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) (Fig. 2 A). As a result, too often the features of recorded SDH neurons, be they projection, excitatory, or inhibitory (Fig. 1), are lumped together to provide an "averaged" view of SDH neuron function. In this examination of the literature, we highlight recent technical advances, which now permit detailed study of SDH neurons with known phenotype, connectivity, ion channel, and receptor biology.
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Characterizing neuronal function throughout the nervous system, including the SDH, routinely involves establishing classes according to morphology, neurotransmitter phenotype, synaptic inputs, and electrophysiological properties. Since the 1980s, this approach has relied heavily on in vitro preparations and has highlighted the considerable heterogeneity in SDH interneuron properties (Fig. 2). For example, in lamina II, four distinct morphological classes are usually identified: islet, central, vertical, and radial cells (Grudt and Perl 2002; Heinke et al. 2004; Melnick et al. 2004a,b). These types differ in the size of their cell bodies and the orientation and extent of their dendritic arbors (Fig. 2B). A similar scheme, also based on cell body size and dendritic orientation, is used to classify lamina I neurons into fusiform, pyramidal, flattened, and multipolar morphologies (Galhardo and Lima 1999; Han et al. 1998; Lima and Coimbra 1986). Electrophysiological studies, on the other hand, have used action potential (AP) discharge to identify different neuronal types: tonic firing, initial bursting, delayed firing, and single spiking (Grudt and Perl 2002; Lopez-Garcia and King 1994; Prescott and De Koninck 2002; Ruscheweyh and Sandkuhler 2002; Thomson et al. 1989). These neurons differ in their discharge responses during depolarizing current injection. Generally, all these types of discharge can be observed in both laminae I and II neurons, although some differences have been reported in the incidence of discharge types between laminae (Ruscheweyh and Sandkuhler 2002).
To date, the task of reconciling various classification schemes for SDH neurons has proved difficult. Both in vitro and in vivo studies have attempted to address this issue by characterizing SDH neurons electrophysiologically but also combining this with intracellular labeling techniques, which allow post hoc analysis of morphology, neurotransmitter phenotype, and other neurochemical characteristics (Grudt and Perl 2002; Han et al. 1998; Hylden et al. 1986; Light et al. 1979, 1993; Melnick et al. 2004a,b; Prescott and De Koninck 2002; Ruscheweyh and Sandkuhler 2002; Steedman et al. 1985; Woolf and Fitzgerald 1983). This approach is labor intensive and has had limited success correlating different SDH neuron properties. To date, correlations have only been described in two studies on lamina I neurons where some of the described morphologies are associated with: AP discharge types in vitro (Prescott and De Koninck 2002) or with specific functional modalities in vivo (Han et al. 1998). Attempts to directly reconcile classifications in lamina II have failed. For example, if we consider AP discharge and morphology, tonic firing is observed in islet, central, and vertical neurons, initial bursting is observed in islet and central neurons, and delayed firing is observed in vertical and radial neurons (Grudt and Perl 2002; Melnick et al. 2004a,b). This limited correspondence between classification schemes used for SDH neurons makes understanding even basic function in this region challenging and calls for new approaches.
DISSECTING SDH NEURON HETEROGENEITY
An alternative to post hoc analyses of neuronal morphology or neurotransmitter phenotype, after electrophysiological characterization, is to directly label subsets of neurons before recording. This approach has particularly use for the SDH where multiple neuronal classes exist, but recognizable cellular organization in fresh tissue is lacking. For example, projection neurons in the SDH can be back-labeled by injecting markers such as DiI (1,1'-didodecyl-3,3,3',3'-tetramethylindo carbocyanine) into specific projection targets of the SDH. Indeed, neurons in lamina I that project to the parabrachial nucleus (PBN) and periaqueductal gray (PAG) have been identified and studied using this technique (Ruscheweyh et al. 2004). Most notably, these projection neurons show two AP discharge patterns not previously reported in other SDH studies (Grudt and Perl 2002; Lopez-Garcia and King 1994; Prescott and De Koninck 2002; Ruscheweyh and Sandkuhler 2002; Thomson et al. 1989). The majority of PBN projecting neurons (
75%) exhibited what the authors termed "gap firing," and most PAG projecting neurons (80%) were either "gap firing or bursting firing" (Ruscheweyh et al. 2004). These findings highlight how recording from neurons with known phenotype (e.g., excitatory projection neurons in Fig. 1) can provide information that would be difficult to obtain using random sampling methods. As the specific ion channels that underlie these unique discharge properties (i.e., gap and bursting firing) of projection neurons are identified, they could be pharmacologically manipulated to reduce excitability in the important "output" neuron of the SDH (see Fig. 1). However, as noted in the previous section, projection neurons constitute only a fraction (<1%) of neurons in the SDH. Unfortunately, the back-labeling approach is not readily applicable to the rest of the SDH neuron population because their axons are largely confined within the SDH, extending at most, over a few spinal cord segments.
Subpopulations of SDH interneurons have recently been identified through production of transgenic mice, where the green florescent protein (GFP) gene is inserted under control of promoters that restrict GFP expression to subsets of neurons (Fig. 3A). One of the first applications of this technique in the SDH took advantage of a mouse prion promoter that provided high expression levels of transgene-encoded polypeptides (in this case GFP) in heart and brain tissue (Borchelt et al. 1996). Although the resulting transgenic mouse was originally used to identify noradrenergic neurons in the locus coeruleus (van den Pol et al. 2002), a number of other cell populations including some lamina II neurons were serendipitously labeled. The GFP-labeled population in the SDH was almost exclusively GABAergic and could be activated during noxious peripheral stimulation of C-fibers (Hantman et al. 2004). Furthermore, all GFP-positive neurons exhibited tonic firing and were morphologically identified as central neurons. Thus for the first time, neurotransmitter phenotype, discharge pattern, and morphology were correlated in a population of SDH neurons (Fig. 3A, left). It is tempting to suggest these neurons share a common function in the SDH; however, further study is needed to test this hypothesis.
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; Zeilhofer et al. 2005). Unlike the findings of the prion promoter study, targeted GABAergic and glycinergic interneurons were not homogeneous (Fig. 3A, right). The GABAergic-GFP neurons exhibited a variety of discharge patterns and were morphologically identified as either islet or central neurons. In addition, these neurons co-expressed a variety of neuroactive substances (i.e., glycine, parvalbumin, or NO), and received monosynaptic or polysynaptic input mediated by A- or C-fibers or both. Similarly, targeted glycinergic-GFP neurons exhibited a range of discharge patterns although neuronal morphology and neurochemical co-localization were not studied (Zeilhofer et al. 2005). These studies indicate that, within the two major inhibitory neuron classes, subpopulations exist with potentially different roles in SDH function. Thus far, it seems that only when these smaller subpopulations of SDH neurons are studied is there a likelihood of resolving discrete neuronal classes and ultimately their specific functions.
Surprisingly, only inhibitory (GABAergic or glycinergic) interneurons in the SDH have been studied using the transgenic labeling approach, even though they constitute 30% of neurons in this region (Polgar et al. 2003; Todd and Sullivan 1990). In fact, excitatory interneurons, which presumably use glutamate as a neurotransmitter, make up the remainder of the SDH neuron population. Study of these excitatory interneurons using transgenic labeling techniques will be important for understanding how the majority of SDH neurons contribute to signal processing. Much like their GABAergic counterparts, studies using promoters tying GFP expression exclusively to the glutamatergic phenotype are unlikely to resolve discrete subpopulations with common features. Instead, glutamatergic interneurons may be divided into subpopulations according to their somatostatin, neurotensin, or enkephalin and substance-P content (Antal et al. 1991; Todd and Spike 1993; Todd et al. 2003). It is as yet unknown if these are truly homogeneous subpopulations. Linking GFP expression to other markers, such as the neuropeptides mentioned above, within the SDH glutamatergic population may be a more effective approach for uncovering different functional groups of excitatory interneurons.
PAIRED RECORDINGS AND SDH NEURON CONNECTIVITY
As discrete populations of SDH neurons are uncovered and specific functional roles are sought, the next challenge is to acquire detailed information about their connectivity. The gold-standard technique for studying connectivity is to make simultaneous "paired" patch-clamp recordings from neurons in a slice preparation. This allows detailed study of synaptically coupled neurons together with their morphology, electrophysiological properties, and synaptic physiology (Fig. 3B). Two meticulous studies recently published by Lu and Perl (2003, 2005) described the results of paired recordings made in the SDH. In both studies, just >10% of the recorded pairs were connected. These connections were unidirectional with approximately equal proportions being inhibitory or excitatory.
Inhibitory connections showed a single configuration, linking islet to central neurons in lamina II through a monosynaptic GABAergic synapse. Both pre- and postsynaptic neurons received monosynaptic C-fiber primary afferent input, although the inputs studied always arrived first at the presynaptic neuron. Tentatively, one could conclude that this connection allows the inhibitory presynaptic islet neuron to reduce excitation in the "downstream" postsynaptic central neuron during a barrage of primary afferent input (Fig. 3B). Without information on the modality of the primary afferent input and the target of the central neuron, the function of this circuit is still only speculative; however, a role in processing different sensory modalities that could "gate" certain peripheral signals is certainly one interpretation.
Unlike inhibitory connections (i.e., always islet to central), excitatory connections varied in the Lu and Perl studies. Two types of connection, however, were repeatedly observed and proposed as defining a "circuit" (Fig. 3B). In lamina II, central neurons excited vertical neurons, and they in turn excited neurons in lamina I, some of which were identified as presumptive projection neurons. The central and lamina I neurons received C-fiber primary afferent input, whereas vertical neurons received A-fiber input. These two connections (central to vertical and vertical to projection) potentially form a circuit capable of processing mixed primary afferent inputs and subsequently relaying signals out of the SDH through lamina I projection neurons. Interestingly, the inhibitory connection (islet to central) described above is compatible with these excitatory connections because the central neuron is common to both circuits. Thus these types of data move us from knowing little about connectivity within the SDH to a possible four-neuron circuit that is crucial to SDH function (Fig. 3B).
If further evidence supports the contributions of Lu and Perl's SDH "connectivity modules" to nociceptive processing, attention should be directed toward vertical and islet neurons in lamina II. For example, decreasing the excitability of vertical neurons would be a reasonable strategy for modulating nociceptive processing because these neurons are critical for transmitting information to lamina I projection neurons. Alternatively, increasing the excitability of islet neurons would be another option because these neurons contribute inhibition to the circuit and effectively reduce excitation of projection neurons. These examples show how detailed knowledge of SDH neuronal connectivity and phenotype, obtained by paired recording, can uncover new avenues for spinal cord–based pain therapies.
Currently, the major limitation of paired recording in the SDH has been the low probability of encountering coupled neurons (10%) and the relatively small data sets (often <20 pairs) in these technically challenging studies. This further reinforces the difficulty of identifying connectivity patterns in the SDH and suggests that without further methodological advances such knowledge will remain difficult to obtain. A new search strategy (Santos et al. 2007) for obtaining paired recordings may prove valuable. This technique establishes whole cell recording in one neuron and tests multiple surrounding neurons for connectivity using a "loose" cell-attached configuration. This modified search strategy has yielded similar SDH connectivity to the Lu and Perl studies (10% of pairs tested), but increased the number of pairs available for analysis (n = 102 vs. n = 28 and n = 44, respectively). Interestingly, the major finding in this study was that a far greater proportion of connections were excitatory (85% vs. 50%). This discrepancy shows the relative infancy of connectivity studies and highlights the important, but still poorly understood, role for excitatory interneurons in SDH function. Perhaps the lack of emphasis on excitatory interneurons is an inadvertent consequence of Melzak and Wall's original gate theory (Melzack and Wall 1965), which emphasized the role of inhibitory circuits in "maintaining the gate" in the SDH. Excitatory interneurons, if only by sheer numbers, must have an equally important role in regulating the output of the SDH. Decreasing the excitability of this particular neuronal population would also represent a promising approach to pain therapy.
ROLE OF SDH NEURONS IN THE INTACT ANIMAL
As outlined above, a large body of in vitro literature describes SDH interneurons according to a host of features (see SDH INTERNEURON HETEROGENEITY AND FUNCTION IN PAIN CIRCUITS). Until recently, functional study of SDH neuron responsiveness in deeply anesthetized rodents was almost exclusively restricted to the use of extracellular recording techniques. Despite being a well-established tool for mapping pathways and major circuitry, extracellular recordings only provide information on suprathreshold responses (AP firing). These recordings do not permit study of: subthreshold synaptic inputs (excitatory or inhibitory); neuron responses to current injection; or morphology of dye-filled neurons (Margrie et al. 2002). Moreover, the technique is biased toward tonically active neurons (Graham et al. 2004). The recent application of the patch-clamp recording technique to SDH neurons in deeply anesthetized rodents (Furue et al. 1999; Graham et al. 2004; Light and Willcockson 1999) now permits collection of all of the above data, plus functional testing of findings made in spinal cord slices. Although there are only a few studies to date, in vivo patch-clamp work in the spinal cord has provided important new insights that challenge some of the conclusions obtained in slice work. This highlights the need for combining in vitro and in vivo approaches to further understand processing mechanisms in SDH.
Since the inception of in vitro spinal cord preparations and patch-clamp recording techniques, one property that has been extensively studied is the response of SDH neurons to current injection (Grudt and Perl 2002; Lopez-Garcia and King 1994; Prescott and De Koninck 2002; Ruscheweyh and Sandkuhler 2002; Thomson et al. 1989; Yoshimura and Jessell 1989). Despite significant efforts, establishing a functional role for tonic firing, initial bursting, delayed firing, and single spiking neurons in vivo has not been achieved. Studies have only drawn tenuous conclusions about the possible role of various discharge patterns in processing sensory information of different modalities. In an attempt to clarify some of these issues, our group recently used in vivo patch-clamp recording in mice to directly test the relationship between SDH neuron responses to similar current injection together with those evoked by noxious (pinch) and innocuous (brush) cutaneous stimulation (Graham et al. 2004). We showed that the in vivo responses of SDH neurons to current injection fell into the four major categories much the same as those routinely described in slice studies (tonic firing, initial bursting, delayed firing, and single spiking). These discharge patterns, however, did not predict the response of an SDH neuron to different forms of cutaneous stimulation. Rather, neurons expressing each of the four discharge patterns could participate in the processing of both noxious and innocuous modalities. Furthermore, despite the clear differences in tonic firing and initial bursting responses evoked by depolarizing current injection, the AP discharge evoked by noxious stimulation (pinch) were remarkably similar. On reflection, this finding is perhaps understandable, given that a depolarizing current step provides a conductance change that has vastly different temporal characteristics to those received by neurons during noxious peripheral stimulation in vivo. We have since established that the tendency of initial bursting neurons to behave like tonic firing neurons during nociceptive signaling in vivo depends critically on the presence of superimposed rapid transients within the injected current waveform, a characteristic of the excitation received by SDH neurons during in vivo pinch stimulation (Graham et al. 2007).
Numerous extracellular recording studies have shown that stimulation of various midline brain stem structures, such as the rostroventral medial medulla (RVM), can alter AP discharge in SDH neurons (Fields et al. 2006; Gebhart 2004; Mason 2005; Millan 2002). The neurotransmitters that mediate the antinociceptive effects originating in RVM are, however, unclear, because several studies have challenged the classically held view that descending inhibition is predominantly serotonergic (Gao and Mason 2000; Gao et al. 1997; Kalyuzhny and Wessendorf 1998). Recently, in vivo patch-clamp recordings have reproduced these results showing that RVM stimulation reduces responses in SDH neurons to noxious (pinch) stimuli in 6 of 10 neurons (Kato et al. 2006). In addition, because patch-clamp recordings were used, the precise synaptic mechanisms underlying descending control of antinociception were also studied. RVM stimulation increased inhibitory drive to SDH neurons through monosynaptic GABAergic and glycinergic RVM projections (Kato et al. 2006) (Fig. 3C). This finding holds promise for selective pain therapy targets, because the GABAA receptor is pharmacologically among the best characterized of all ligand-gated ion channels and has considerable diversity in its subunit composition (Johnston 2005; Mody and Pearce 2004; Rudolph and Mohler 2006), raising the possibility that these channels could be selectively modulated in the spinal cord. Future experiments using such in vivo preparations will allow detailed and direct testing of therapeutic agents on descending antinociceptive mechanisms in the SDH.
CONCLUSIONS AND FUTURE DIRECTIONS
The challenge remains for spinal cord–based pain research to understand the precise mechanisms determining excitability in the SDH and specifically modulate these mechanisms with therapeutic agents (Fig. 1). Like other regions of the nervous system, three general properties ultimately govern SDH neuronal excitability: 1) excitatory synaptic inputs; 2) inhibitory synaptic inputs; and 3) intrinsic membrane properties. Importantly, there is now abundant evidence that disruption in any of the above properties can alter neuronal excitability in the SDH and lead to the development and maintenance of chronic pain states. When this evidence is coupled with recent advances in ion channel and receptor biology, it becomes feasible to specifically target therapies aimed at each of these three major mechanisms that regulate neuronal excitability in the SDH. For example, one type of Ca2+-permeable glutamate receptor (GluR-A) is highly expressed in the SDH (Hartmann et al. 2004). This form of the receptor is implicated in altered pain states and hence compounds that specifically antagonize GluR-A represent a potential therapeutic opportunity. Likewise, a novel form of the glycine receptor (GlyR) is distinctly expressed in the SDH (Harvey et al. 2004). These GlyRs contain 
3 subunits and are selectively inhibited by the action of prostaglandin E2 (PGE2). Interestingly, PGE2 does not affect the ubiquitous 1 subunit-containing form of the GlyR. Compounds that selectively potentiate the function of 3 GlyRs or block the PGE2 pathway may again present a promising approach to pain therapy (Zeilhofer 2005a). Finally, a family of voltage-gated K+channels, which mediate A-type potassium currents, are also important determinants of neuronal excitability and are concentrated in the SDH. Genetic elimination of one type (Kv4.2) increases SDH neuronal excitability and enhances the onset of chronic pain (Hu et al. 2006). Potentiating the function of this channel would have the inverse effect of decreasing neuronal excitability and reducing pain. The precise distribution of these promising molecular targets (i.e., channels containing GluR-A, 3GlyR, and Kv4.2 subunits) on the different types of neurons in the SDH, however, remains to be determined. This information will be vital for future drug design, as illustrated by the SDH circuitry in Fig. 1 which shows the importance of understanding the distribution of these ion channels on major neuronal types. For example, it would be of little use designing a drug that antagonizes the Kv4.2 potassium channel if these channels were confined to excitatory interneurons, because this would presumably increase overall excitability of the SDH and decrease pain thresholds.
In summary, techniques developed in the past decade are dramatically increasing our knowledge of SDH neuronal types, their connectivity, and their behavior in intact animals. As more information becomes available particularly from use of the techniques highlighted in this review, it is of limited use to maintain an "averaged" view of SDH neuron function when assessing potential pain therapies. The challenge now is to consider this new detailed information in light of the ever-expanding number of molecular targets being proposed for chronic pain therapies (Gilron and Coderre 2007; Lynch and Callister 2006; Zeilhofer 2005b). Specifically, we must now establish the distribution of relevant molecular targets on specific neuronal types in defined SDH circuits so they can be selectively targeted to manipulate excitability and transmission of pain signals through the spinal cord.
Address for reprint requests and other correspondence: R. J. Callister, School of Biomedical Sciences, Faculty of Health, Univ. of Newcastle, Callaghan, NSW 2308, Australia (E-mail: robert.callister{at}newcastle.edu.au)
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