Figure 6

Working hypothesis for the tonic inhibition of spinal pain by nicotinic cholinergic transmission through primary afferents. The cholinergic primary afferents terminating in the spinal dorsal horn tonically activate nicotinic acetylcholine receptors on GABAergic interneurons through acetylcholine synthesis and release. Due to maximal activation of this network, exogenously administered nicotine has no effect in the normal state. On the other hand, in the ChAT knock-down state, the thresholds of pain mechanisms are reduced because of the loss of this tonic pain inhibition system, and exogenously applied nicotine can activate nAChRs leading to analgesia. The physiological role of ACh in DRG neurons is as a modulator of pain transmission to avoid hyperexcitability of spinal sensory neurons.