PrefaceNeurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics, and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organisation and circuitry of this complex region.Dorsal horn neurons receive sensory information from primary afferents that innervate the skin and deeper tissues of the body and that respond to specific types of noxious and nonnoxious stimuli. These afferents terminate in the dorsal horn with a distribution pattern that is determined by their sensory modality and the region of the body that they innervate. The incoming information is processed by complex circuits involving excitatory and inhibitory interneurons, and transmitted to projection neurons for relay to several brain areas. In addition, nociceptive information is conveyed to the ventral horn and contributes to spinallymediated nocifensive reflexes 1 . Activity at various points in these circuits can be modulated by axons that descend from the brainstem.The balance between excitation and inhibition is critical for maintaining normal sensory function -blocking inhibitory transmission at spinal levels, for example, can lead to allodynia 1,2 . Indeed, changes in the function of these circuits have been implicated in the development and maintenance of inflammatory and neuropathic pain.Despite the importance of the dorsal horn in normal sensory processing and in pathological conditions, we still know little about the neuronal circuits that link incoming primary afferents to projection neurons, which constitute its major output. The main reason for this is that the great diversity of dorsal horn neurons has made it difficult to develop a comprehensive classification scheme for either the interneurons or the projection cells. Without such a scheme it is not possible to establish the roles of different neurons within these circuits.In this review I describe the basic neuronal components of the dorsal horn and what we know about the circuits in which they are involved, with particular emphasis on pathways that process nociceptive information. This description will be restricted to laminae I-III of Rexed 3 (Figure 1), as we know more about the organisation of this region than that of the deeper laminae. Moreover, this region includes the major termination zone of nociceptive primary afferents (laminae I and IIo). I also discuss changes that could underlie the abnormal sensations that arise following tissue inflammation and in cases of neuropathic pain. The review is based mainly on findings in the rat, as the majority of th...

Lamina II contains a large number of interneurons involved in modulation and transmission of somatosensory (including nociceptive) information. However, its neuronal circuitry is poorly understood due to the difficulty of identifying functional populations of interneurons. This information is important for understanding nociceptive processing and for identifying changes that underlie chronic pain. In this study, we compared morphology, neurotransmitter content, electrophysiological and pharmacological properties for 61 lamina II neurons recorded in slices from adult rat spinal cord. Morphology was related to transmitter content, since islet cells were GABAergic, while radial and most vertical cells were glutamatergic. However, there was considerable diversity among the remaining cells, some of which could not be classified morphologically. Transmitter phenotype was related to firing pattern, since most (18/22) excitatory cells, but few (2/23) inhibitory cells had delayed, gap or reluctant patterns, which are associated with A-type potassium (IA) currents. Somatostatin was identified in axons of 14/24 excitatory neurons. These had variable morphology, but most of those tested showed delayed-firing. Excitatory interneurons are therefore likely to contribute to pain states associated with synaptic plasticity involving IA currents. Although noradrenaline and serotonin evoked outward currents in both inhibitory and excitatory cells, somatostatin produced these currents only in inhibitory neurons, suggesting that its pro-nociceptive effects are mediated by disinhibition. Our results demonstrate that certain distinctive populations of inhibitory and excitatory interneuron can be recognised in lamina II. Combining this approach with identification of other neurochemical markers should allow further clarification of neuronal circuitry in the superficial dorsal horn.

SummaryMenthol and other counterstimuli relieve itch, resulting in an antipruritic state that persists for minutes to hours. However, the neural basis for this effect is unclear, and the underlying neuromodulatory mechanisms are unknown. Previous studies revealed that Bhlhb5−/− mice, which lack a specific population of spinal inhibitory interneurons (B5-I neurons), develop pathological itch. Here we characterize B5-I neurons and show that they belong to a neurochemically distinct subset. We provide cause-and-effect evidence that B5-I neurons inhibit itch and show that dynorphin, which is released from B5-I neurons, is a key neuromodulator of pruritus. Finally, we show that B5-I neurons are innervated by menthol-, capsaicin-, and mustard oil-responsive sensory neurons and are required for the inhibition of itch by menthol. These findings provide a cellular basis for the inhibition of itch by chemical counterstimuli and suggest that kappa opioids may be a broadly effective therapy for pathological itch.

To effect movement, motoneurons must respond appropriately to motor commands. Their responsiveness to these inputs, or excitability, is regulated by neuromodulators. Possible sources of modulation include the abundant cholinergic ''C boutons'' that surround motoneuron somata. In the present study, recordings from motoneurons in spinal cord slices demonstrated that cholinergic activation of m 2-type muscarinic receptors increases excitability by reducing the action potential afterhyperpolarization. Analyses of isolated spinal cord preparations in which fictive locomotion was elicited demonstrated that endogenous cholinergic inputs increase motoneuron excitability during locomotion. Anatomical data indicate that C boutons originate from a discrete group of interneurons lateral to the central canal, the medial partition neurons. These results highlight a unique component of spinal motor networks that is critical in ensuring that sufficient output is generated by motoneurons to drive motor behavior.T o generate movement, it is necessary for motoneurons (MNs) to integrate the inputs (motor commands) they receive and produce an output sufficient to effect muscular contraction. The relationship of input to output is determined by neuronal excitability, which in the case of MNs is known to be regulated by identified descending modulatory systems (1). Given that these descending systems are disrupted after spinal cord injury, strategies aimed at restoring movement need to address not only premotor circuits that provide motor commands but also any modulatory systems that ensure MNs are sufficiently excitable to respond to these commands. Spinal premotor circuits for locomotion can be activated after spinal transection (2) and provide one clear target for treatments designed to produce functional recovery. Should an intrinsic spinal modulatory system exist, this would be an important additional target for such strategies.The somata and proximal dendrites of MNs are contacted by large cholinergic varicosities named ''C boutons'' (3-11). It has been known since 1972 (12) that C boutons originate from spinal cord neurons, but the location of these cells remains unknown (10). Although the C bouton synapse has been anatomically characterized and shown to be associated with postsynaptic type 2 muscarinic (m 2 ) receptors (8-10), neither the physiological effects of m 2 receptor activation on MNs nor the roles of C boutons in motor activity are known. In the absence of motor behavior, exogenous application of cholinergic agonists affects MN excitability via undefined mechanisms (13-17). We therefore studied the possibility that the intrinsic spinal neurons that give rise to the C boutons regulate MN excitability via activation of m 2 receptors, and that this system is used during motor behavior. ResultsThe Effects of Muscarinic Receptor Activation on Spinal MNs. Because C boutons are closely associated with postsynaptic m 2 receptors by the second postnatal week (8-10), we investigated the effects of muscarinic receptor activatio...

The distributions of GABA-like and glycine-like immunoreactivities in the rat spinal cord were compared by using postembedding immunohistochemistry on semithin sections. In laminae I, II, and III, the proportions of GABA immunoreactive cells were 28%, 31%, and 46%, respectively, whereas for glycine immunoreactive cells the proportions were 9%, 14%, and 30%. Nearly all of the glycine immunoreactive cells in this area were also immunoreactive with the anti-GABA antiserum. In lamina II, some Golgi-stained islet cells were glycine immunoreactive, whereas others were not. Immunoreactive cell bodies were also present in the remainder of the grey matter. Some of these reacted with anti-GABA or antiglycine antiserum; others showed immunoreactivity with both antisera. Immunoreactive axons were found in the ventral and lateral funiculi of the white matter. Many large axons reacted with antiglycine antiserum, whereas GABA-immunoreactive axons were mostly of small diameter. Some large and small axons showed both types of immunoreactivity. These results suggest that the inhibitory neurotransmitters GABA and glycine coexist within cell bodies and axons in the rat spinal cord.