Moving From an Averaged to Specific View of Spinal Cord Pain Processing Circuits

Abstract

Graham BA, Brichta AM, Callister RJ. Moving from an averaged to specific view of spinal cord pain processing circuits. J Neurophysiol 98: [1057][1058][1059][1060][1061][1062][1063] 2007. First published June 13, 2007; doi:10.1152/jn.00581.2007. 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. I N T R O D U C T I O NThe 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 ascend...

Evidence for a Critical Period in the Development of Excitability and Potassium Currents in Mouse Lumbar Superficial Dorsal Horn Neurons

“…exploring the role of genes in pain mechanisms (Graham et al 2007a;Harvey et al 2004), it is important to know when the electrophysiological properties of SDH neurons can be considered stable or "adultlike" in this species. Our data show that many electrophysiological properties change in SDH neurons during the developmental period examined (E15-P25).…”

Estrogenic influences in pain processing

“…These interneurons play a key role in the processing of nociceptive stimuli and in setting the overall "excitability level" in the spinal dorsal horn (Fields and Basbaum, 2005;Graham et al, 2007) (Fig. 3B).…”

“…In lamina II, interneurons containing enkephalin and other neuropeptides may affect primary afferent nociceptive transmission pre-or postsynaptically. Adapted from Craig, 2003a. Approximately 30% of these neurons are inhibitory whereas the remainder is excitatory (Graham et al, 2007). These interneurons, which are preferentially located in lamina II, are under the control of powerful descending inhibitory or facilitating pathways with a supraspinal origin.…”

Genetically Defined Inhibitory Neurons in the Mouse Spinal Cord Dorsal Horn: A Possible Source of Rhythmic Inhibition of Motoneurons during Fictive Locomotion

“…Given the location of these superficial GABAergic interneurons, it is possible that they are associated with local afferent processing such as inhibitory transmission to substantia gelatinosa neurons (Yoshimura and Nishi, 1995). It has been shown that small inhibitory cells in the superficial dorsal horn are mostly related to processing ascending sensory information by modulating neurotransmitter release from the central terminals of primary afferents (Lao and Marvizon, 2005) and being the substrate for lateral inhibition in ascending sensory systems (Le Bars, 2002;Heinke et al, 2004;Graham et al, 2007). Heinke et al (2004) suggested that GFP-positive cells in laminae I and II in GAD67-GFP transgenic mice are involved in the transmission of nociceptive information to the brain.…”