A ‘SIC’ and painful story

Acute tissue injury produces nociceptive pain. Because it promotes avoidance of tissue damage, this unpleasant, yet vital physiological response ensures the survival of the species. By contrast, neuropathic pain induced by injury to, or disease of, the somatosensory system is a major health problem. Neuropathic pain and some types of chronic inflammatory pain involve ‘central sensitization’. This is reflected as a heightened response to painful stimuli (hyperalgesia) and perception of innocuous stimuli as painful (allodynia). ‘Central sensitization’ typically starts in the spinal dorsal horn but is later manifest as an enduring change in the supraspinal and cortical structures that contribute to pain perception. It is now established that the initiation of ‘central sensitization’ at the spinal level involves a transient increase in the level of microglial activation. Communication between primary afferents, microglia and astrocytes is effected by a range of cytokines, growth factors, neuropeptides and ATP. Whereas microglial activation triggers pain onset, enduring activation of astrocytes is thought to be responsible for the maintenance of chronic pain (Marchand et al. 2005; Scholz & Woolf, 2007; Sandkuhler, 2009). If this is so, output of nociceptive information from the dorsal horn must require dialogue between activated astrocytes and neurons. A paper in this issue of The Journal of Physiology by Bardoni et al. (2010) provides new insights into the mechanism of this clinically relevant example of ‘gliotransmission’. Recordings of spontaneous synaptic activity in dorsal horn neurons are occasionally interrupted by spontaneous, slow inward currents (SICs) which are larger and much slower than spontaneous and/or miniature EPSCs. Figure 1 shows an example of a SIC recorded in a lamina II neuron in our laboratory. The SIC is double the amplitude and 1000-fold slower than a typical spontaneous EPSC. Bardoni et al. have shown that SICs result from glutamate-mediated ‘gliotransmission’ between astrocytes and neurons. Importantly, and in the context of chronic pain mechanisms, it was found that the hyperalgesia associated with inflammation was correlated with an increase in the number of neurons exhibiting SICs. Whole-cell voltage-clamp recording of spontaneous activity in a lamina II neuron held at −70 mV The animal had actually been subject to 14 days sciatic chronic constriction injury as part of another study. Trace illustrates one spontaneous, large SIC and numerous spontaneous EPSCs (sEPSC), one of which is illustrated on a fast time scale for comparison with the SIC. The approach involved study of spinal cord slices isolated from control animals and those subject to 6–8 days peripheral inflammation following subcutaneous injection of Zymosan A. The extent of inflammation was monitored by plethysmometry and the onset of hyperalgesia monitored by the standard Hargreve's test for thermal hyperalgesia and von Frey filaments for mechanical hyperalgesia. Activity of astrocytes and neurons in Lamina II were monitored by whole-cell recording and confocal Ca2+ imaging. It was found that stimulation of astrocytes by activation of P2X7 receptors, or surprisingly, by low extracellular Ca2+ significantly increased the number of control neurons exhibiting SICs. These were insensitive to the AMPA antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; 10 μm) but were almost completely blocked by the NMDA blocker d(–)-2-amino-5-phosphonopentanoic acid (d-AP5; 100 μm). The ability of activated astrocytes to produce a ‘domain response’ in a group of neurons was demonstrated by careful temporal monitoring of astrocytic and neuronal Ca2+ responses. In the example in the paper, the authors show that superfusion of the P2X7 agonist 2′(3′)-O-(4-benzoylbenzoyl)adenosine 5′-triphosphate triethylammonium salt (BzATP) activated three astrocytes in their field of view and this was followed by the synchronous activation of five neurons. Every time the astrocytes were activated, the same five neurons responded with synchronous increases of intracellular Ca2+. The authors also showed that peripheral inflammation promoted a 3-fold increase in the number of neurons that exhibited SICs. The study thus provides a mechanistic basis for a link between astrocyte activation and the persistent activity of dorsal horn neurons that underlies ‘central sensitization’. The synchrony of neuronal activation associated with SICs may explain the shooting pains sometimes experienced by chronic pain patients and the participation of NMDA receptors may explain the effectiveness of antagonists such as ketamine in some types of chronic pain. Of course, numerous questions still remain. For example, SICs are quite rare, and occur at <0.01 Hz in 44% of neurons in the inflammatory model used. Is this amount of activity sufficient to contribute to central sensitization? Might more SICs be seen in neuropathic pain or in more chronic models of inflammatory pain? The authors also did not determine which neuron types displayed SICs; if these occur in inhibitory interneurons, they may actually reduce rather than increase spinal network activity. Although we now have a good working knowledge of the mechanisms associated with the onset of central sensitization, much less is known about the maintenance of chronic pain (Marchand et al. 2005; Scholz & Woolf, 2007; Sandkuhler, 2009). Despite its shortcomings, the study of Bardoni et al. provides important clinically relevant insight, because chronic pain patients, by definition, present in the maintenance phase rather than in the onset phase of pain.

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