Commentary Feed - forward inhibition : a novel cellular mechanism for the analgesic effect of substance

Substance P (SP) is a neuropeptide well known for its contribution to pain transmission in the spinal cord, however, less is known about the possible modulatory effects of SP. A new study by Gu and colleagues, published in Molecular Pain (2005, 1:20), describes its potential role in feed-forward inhibition in lamina V of the dorsal horn of the spinal cord. This inhibition seems to function through a direct excitation of GABAergic interneurons by substance P released from primary afferent fibers and has a distinct temporal phase of action from the well-described glutamate-dependent feedforward inhibition. It is believed that through this inhibition, substance P can balance nociceptive output from the spinal cord. The spinal cord dorsal horn is one of the relay stations for nociceptive information transmitted by peripheral sensory afferents. Some of these sensory afferents are substance P (SP) and glutamate-containing Aδand Cfibers. Upon noxious stimulation, particularly intense stimulation, tachykinins such as SP and neurokinin A (NKA) are released from primary afferent fibers and excite dorsal horn neurons via activation of the neurokinin-1 and neurokinin-2 receptors (NK1R and NK2R), respectively [1,2]. A series of studies have established a role for SP in the transmission of pain information [3,4]. Mice genetically engineered not to express the precursor of SP [4] and mice that do not express SP's target, the NK1R [3], both display reduced responses to painful stimuli. Despite these promising initial findings, NK1R antagonists have failed to produce analgesia in a variety of clinical pain models [5]. One possible explanation for these inconsistent results is that SP may produce mixed effects in sensory-related transmission and modulation. Indeed, Mohrland and Gebhart reported that an intrathecal injection of SP had antinociceptive effects [6]. Similarly, a study has found an analgesic effect mediated by SP and further suggested that it might be mediated by μ-2 opioid receptors [7]. Other studies demonstrate an interaction between tachykinin and opioid systems, lending support for a role of opioid receptors in SP-mediated antinociception [8]. Although many studies have highlighted the importance of SP in pain transmission, the synaptic mechanisms underlying the antinociceptive effect of SP remain unclear. In a recent study published in Molecular Pain, Gu and colleagues used a combination of electrophysiological, pharmacological, genetic and behavioral techniques in rats and found that SP can modulate inhibitory transmission in lamina V of the spinal cord dorsal horn, thereby exerting an analgesic effect on nociceptive sensory processing [9]. Through this finding, the study provides novel insight into the role of SP in the spinal cord dorsal Published: 18 November 2005 Molecular Pain 2005, 1:34 doi:10.1186/1744-8069-1-34 Received: 29 September 2005 Accepted: 18 November 2005 This article is available from: http://www.molecularpain.com/content/1/1/34 © 2005 Wu et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.