Dissociation of the Opioid Receptor Mechanisms that Control Mechanical and Heat Pain

Abstract

Summary Delta and mu opioid receptors (DORs and MORs) are inhibitory G-protein coupled receptors that reportedly cooperatively regulate the transmission of pain messages by substance P and TRPV1-expressing pain fibers. Using a DOReGFP reporter mouse we now show that the DOR and MOR are, in fact, expressed by different subsets of primary afferents. The MOR is expressed in peptidergic pain fibers, the DOR in myelinated and nonpeptidergic afferents. Contrary to the prevailing view, we demonstrate that the DOR is trafficked to the cell surface under resting conditions, independently of substance P, and internalized following activation by DOR agonists. Finally, we show that the segregated DOR and MOR distribution is paralleled by a remarkably selective functional contribution of the two receptors to the control of mechanical and heat pain, respectively. These results demonstrate that behaviorally relevant pain modalities can be selectively regulated through the targeting of distinct subsets of primary afferent pain fibers.

Knockout subtraction autoradiography: A novel ex vivo method to detect heteromers finds sparse KOP receptor/DOP receptor heterodimerization in the brain

“…In line with our findings, a role for opioid heterodimers in modulating the actions of opioid drug actions requires their co-expression in a single cell, a concept that is controversial and a previous study has failed to find DOPr's, fused with enhance green fluorescent protein in MOPr containing small dorsal root ganglion neurons (Scherrer et al, 2009). Despite the lack of evidence in our study for widespread heterodimerization throughout the brain, the importance of heterodimer formation in a few structures should not be underestimated, and the potential functional role for heterodimerisation in thalamus and amygdala may point to their relevance in pain and emotional behaviours.…”

VGLUT2 expression in primary afferent neurons is essential for normal acute pain and injury-induced heat hypersensitivity

“…Our finding that the cKO mice are less sensitive to acute heat stimuli and intraplantar capsaicin, and do not develop heat hyperalgesia after tissue injury, is consistent with VGLUT2 expression in the peptidergic C fibers, which in the mouse also express the heat-and capsaicin-sensitive TRPV1 channel. In fact, destruction of TRPV1-expressing DRG neurons or their central terminals in the mouse produces a remarkably similar behavioral phenotype-namely, loss of both acute heat pain responsiveness and the sensitization to heat stimuli that occurs with tissue injury (6)(7)(8). We propose, therefore, that heat deficits observed in the cKO mice arise from loss of VGLUT2-dependent glutamate signaling from TRPV1-expressing peptidergic C or Aδ nociceptors.…”

“…We now show that VGLUT2 deletion also reduces sensitivity to noxious mechanical stimuli. Furthermore, specific deletion of a large fraction of IB4+ C nociceptors (6), or intrathecal administration of an agonist of the delta opioid receptor, which is expressed by IB4+ nociceptors (8), also reduces acute mechanical pain responsiveness. Taken together, we suggest that glutamate release from these VGLUT2-expressing IB4+ afferents is critical for-but not the only contributor to-normal responsiveness to noxious mechanical stimuli.…”

“…Not only do subsets of nociceptors express different repertoires of neuropeptides, receptors, and ion channels, but they also project to different laminae in the spinal cord where they engage different CNS circuits (2)(3)(4). Importantly, studies in rodents in which different nociceptor populations have been deleted revealed remarkably selective behavioral deficits (e.g., heat, mechanical, or chemical pain), demonstrating the existence of behaviorally relevant peripheral-labeled lines for different modalities of pain (5)(6)(7)(8).…”

Coexpression of δ- and μ-opioid receptors in nociceptive sensory neurons

“…This distribution of opioid receptors is consistent with DOR-and MOR-mediated inhibition of Ca 2+ currents in small DRG neurons (15,25,26). However, a recent study in the mouse expressing DOR1 with enhanced green fluorescent protein inserted at the C-terminus (DOR1-EGFP) (27) shows that only ∼17% DRG neurons express DOR1-EGFP predominantly in large neurons but not in MOR-or neuropeptideexpressing small DRG neurons (28), suggesting a distinct dissociation of DORs and MORs in primary sensory afferents and pain modulation.…”