The μ‐opioid receptor: an electrophysiologist's perspective from the sharp end

Abstract

Morphine, the prototypical opioid analgesic drug, produces its behavioural effects primarily through activation of μ-opioid receptors expressed in neurones of the central and peripheral nervous systems. This perspective provides a historical view of how, over the past 40 years, the use of electrophysiological recording techniques has helped to reveal the molecular mechanisms by which acute and chronic activation of μ-opioid receptors by morphine and other opioid drugs modify neuronal function. ]-enkephalin; GIRK, G protein-activated potassium conductance; GRK, G protein-coupled receptor kinase; INRC, International Narcotics Research Conference; LC, locus coeruleus; Met Enk, methionine enkephalin; PAG, periaqueductal grey region; VTA, ventral tegmental area This perspective is based on the author's Founders' Lecture delivered at the 2013 International Narcotics Research Conference (INRC). The aim was to review the contribution that electrophysiological recording techniques have made over the past 40 years to elucidating the actions of opioid drugs on neurones of the CNS. This is not intended to be a comprehensive review of μ-opioid receptor (receptor nomenclature conforms to Alexander et al., 2013) pharmacology rather it reflects somewhat the author's scientific journey and so apologies are due to those whose work is not cited. LINKED ARTICLESThis μ-Opioid receptor activation Interaction with potassium and calcium channelsIn the early 1970s experiments using extracellular recording from brain neurones in vivo led to reports such as the following -'Out of 76 neurones studied, morphine [applied by iontophoresis] increased the firing rate of 33 and depressed that of 17. . . . The remaining 26 neurones were unaffected' (Bradley and Dray, 1974, p. 48). It was the introduction of intracellular recording that enabled more sophisticated analysis of opioid action, first with the use of sharp electrode recording of membrane potential and single-electrode voltage clamp then with patch clamp recording of whole-cell and single-channel currents. In the mid-1970s in Aberdeen, the late Hans Kosterlitz, one of the founders of INRC, with great foresight encouraged Alan North and myself to study opioid action by recording from opioid-sensitive neurones. This led to the observation that activation of μ-opioid receptors resulted in membrane hyperpolarization through opening of potassium channels in guinea pig myenteric plexus neurones (North and Tonini, 1977) and guinea pig and rat locus coeruleus (LC) neurones ( Figure 1A; Pepper and Henderson, 1980;Williams et al., 1982).The opioid-activated potassium conductance in LC neurones was subsequently characterized as inwardly rectifying (North and Williams, 1985) and, as the coupling from receptor to channel is through pertussis toxin-sensitive G-proteins, is now referred to as a G-protein-activated inwardly rectifying potassium conductance (GIRK). We now know from studies in other types of neurones that μ-opioid receptors can couple to a variety potassium channels including calcium-acti...

Metformin reduces morphine tolerance by inhibiting microglial-mediated neuroinflammation

“…Among the previous studies, mechanisms of morphine tolerance are complex and involve many factors, such as ion channels, receptors, cells, and neural networks [1–3]. For a long time, extensive studies suggested that neurons participate in the development of morphine tolerance [3, 4].…”

µ-opioid receptor-mediated downregulation of midline thalamic pathways to basal and central amygdala

“…More particularly, the exact cellular and synaptic mechanisms of µ-opioidergic modulation in this dMT-amygdala circuit remain unresolved. At the cellular level, ligand-binding to MORs activates G-protein-coupled inwardly rectifying potassium channels (GIRKs) leading to membrane hyperpolarization 19,20 . It has been proven that neurons in the dMT are inhibited by MOR signaling via this mechanism 21 .…”

Themed section

“…Stefan Schulz's group review their pioneering work (Mann et al ., ) on the development and use of phospho‐site specific antibodies to study homologous and heterologous MOPr regulation, the latter mediated by protein kinase C phosphorylation of MOPr. This could provide an explanation for the protein kinase C (PKC)‐mediated desensitization of MOPr by morphine, when PKC has been activated, as observed in a range of cells (Henderson, ). However, the research paper of Arttamangkul et al .…”

“…The INRC meeting was opened with the traditional Founders Lecture delivered by Graeme Henderson (Henderson, ). The Founders Lecture honours the contributions of individuals who have a made a sustained and substantial contribution to the science upon which the conference is based.…”