Presynaptic control of nociceptor signalling: Differential influence of Mu Opioid and GABAergic Systems

Abstract

It is difficult to pick a topic to discuss that adequately honours Ron Melzack's many years of pain research. This is particularly problematic if one is cognizant of the tremendous emphasis that Ron puts on the distinction between pain and nociception. Indeed, the thread that binds so many of Ron's studies is that the complexity of the pain experience will not be understood if one exclusively concentrates on the processing of nociceptive messages at the level of the periphery or spinal cord. Ron always emphasized the importance of affective and cognitive components of the pain experience. These elements of the pain experience, so beautifully and memorably discussed in Melzack and Casey's (1) theoretical review, must always be included when this topic is addressed. Dr Allan Basbaum was a student of Ron's in an undergradu- The relative contribution of pre-and postsynaptic controls to the flow of nociceptive information at the level of the spinal cord has been one of Ron Melzack's longstanding interests and a key issue in the formulation of the gate control theory. The authors review their own studies, in which they monitored internalization of the neurokinin-1 receptor to examine specifically the action of two classically inhibitory systems -mu opioid and gamma-amino butyric acid (GABA) -on noxious stimulus-evoked tachykinin signalling in the rat spinal cord. Evidence that opioids and GABAergic controls operate differently on the central consequences of any noxious stimulus-induced substance P release is provided. Whereas at least 80% of the tachykinin signalling remained intact after even the highest concentration of spinal morphine or D-Ala2, NMe-phe4, Glyol5-enkephalin administration, spinal administration of the GABA B receptor agonist baclofen had a dramatic inhibitory effect. These findings are discussed in light of the disappointing clinical utility of baclofen and neurokinin-1 receptor antagonists to combat pain. Key Words: Gamma-amino butyric acid; Mu opioid; Neurokinin 1 receptors; Receptor internalization; Spinal cord; TachykininsCommande présynaptique de la transmission des signaux par les nocicepteurs : mécanisme d'action des opioïdes de type mu et du GABA Le rôle relatif des commandes pré-et postsynaptiques dans la transmission des signaux nociceptifs dans la moelle épinière, en plus de susciter l'intérêt soutenu de Ron Melzack, a constitué un pilier de la théorie du ‹‹ portillon ››. Les auteurs ont passé en revue leurs propres études dans lesquelles ils se sont penchés sur l'endocytose des récep-teurs de la neurokinine 1 afin d'étudier le mécanisme d'action de deux inhibiteurs classiques, les opioïdes de type mu et l'acide gammaaminobutyrique (GABA), sur la transmission de la tachykinine déclen-chée par un stimulus nocif dans la moelle épinière du rat. Ils ont recueilli des preuves selon lesquelles les opioïdes et le GABA agissent différemment sur les effets centraux de la libération de la substance P, provoquée par un stimulus nocif. Tandis qu'au moins 80 % de la transmission des signaux par la tac...

On the recovery of disorders of consciousness under intrathecal baclofen administration for severe spasticity—An observational study

“…Another possible and less discussed route of action of ITB contributing to improved awareness and cognition may be an ITB-related reduction in pain transmission. At the spinal level, there is evidence of an inhibitory action of ITB on nociceptor activity via presynaptic action at GABA B receptors located on small-diameter nociceptive afferents reaching the superficial dorsal horn (Riley et al, 2000). ITB exerted clinical analgesic effects on neuropathic pain in spinal cord injury patients both in open as well as randomized placebo-controlled trials (Kumru et al, 2013(Kumru et al, , 2018, with long-lasting benefit (Kumru et al, 2020).…”