Gain control mechanisms in the nociceptive system

Abstract

The "gate control theory of pain" of 1965 became famous for integrating clinical observations and the understanding of spinal dorsal horn circuitry at that time into a testable model. Although it became rapidly clear that spinal circuitry is much more complex than that proposed by Melzack and Wall, their prediction of the clinical efficacy of transcutaneous electrical nerve stimulation and spinal cord stimulation has left an important clinical legacy also 50 years later. In the meantime, it has been recognized that the sensitivity of the nociceptive system can be decreased or increased and that this "gain control" can occur at peripheral, spinal, and supraspinal levels. The resulting changes in pain sensitivity can be rapidly reversible or persistent, highly localized or widespread. Profiling of spatio-temporal characteristics of altered pain sensitivity (evoked pain to mechanical and/or heat stimuli) allows implications on the mechanisms likely active in a given patient, including peripheral or central sensitization, intraspinal or descending inhibition. This hypothesis generation in the diagnostic process is an essential step towards a mechanism-based treatment of pain. The challenge now is to generate the rational basis of multimodal pain therapy algorithms by including profile-based stratification of patients into studies on efficacy of pharmacological and nonpharmacological treatment modalities. This review outlines the current evidence base for this approach.

Identification of spinal circuits involved in touch-evoked dynamic mechanical pain

“…Mechanical hypersensitivity induced by nerve injury or inflammation is caused by both neuronal sensitization and disinhibition 9–12 . To assess if the VT3 Lbx1 neurons mediate mechanical hypersensitivity induced purely by disinhibition, we performed intrathecal injection of bicuculline and strychnine to inhibit GABA A and glycine receptors, respectively.…”

“…Following nerve injury or inflammation, central sensitization and/or disinhibition opens the “gate”. This opening allows subthreshold inputs from low threshold mechanoreceptors (A-LTMRs or C-LTMRs) to induce action potential firing in laminae I/II o output neurons 10–12,45 , causing a drastic drop in withdrawal thresholds. The recruitment of LTMR-mediated new pain pathways could then explain why VT3 Lbx1 neurons are largely dispensable for transmitting punctate hypersensitivity following nerve lesion or inflammation, despite being required to transmit acute light punctate mechanical stimuli.…”

“…According to this theory, spinal pain transmission neurons receive inputs from both nociceptors and low threshold mechanoreceptors (LTMRs), with LTMR inputs being gated by feedforward inhibition 3–8 . In chronic pain conditions caused by nerve lesions or inflammation, attenuation of this feedforward inhibition plus sensitization of primary and relay neurons opens the gate, allowing LTMR inputs to activate pain transmission neurons and allodynia manifestation to occur 9–12 . Allodynia exists in multiple forms in humans, including dynamic, static, and punctate.…”

The model of the Nociceptive Withdrawal Reflex in horses

“…Analgesic activity is generally attributed to a drug when a substantial increase in nociceptive thresholds occurs after its administration (Le Bars et al 2001). The NWR model does not simply allow to precisely recognize an increase in threshold, but it also permits to describe the pharmacologically induced changes in shape of the stimulus-response curve, providing interesting additional information compared to classical nociceptive tests (Treede 2016). Nevertheless, as other nociceptive tests, the NWR depends on a sensory and a motor component.…”

“…The model of the Nociceptive Withdrawal Reflex in horses C. Spadavecchia et al activity and on the drug-related changes in the gain of the nociceptive system (Spadavecchia et al 2007, Treede 2016.…”