Kappa opioids inhibit the GABA/glycine terminals of rostral ventromedial
medulla projections in the superficial dorsal horn of the spinal cord
Abstract
Background and Purpose: Descending projections from neurons in the
rostral ventromedial medulla (RVM) make synapses within the superficial
dorsal horn of the spinal cord that is involved in acute nociception and
the development of chronic pain and itch. In addition, this projection
plays an important role in mediating the analgesic effects of opioids.
However, our knowledge about the spinal synaptic targets of RVM
projections and their modulation by opioids is unknown. Experimental
Approach: We used ex vivo optogenetic stimulation of RVM
descending fibres and whole-cell patch-clamp recordings from superficial
dorsal horn (SDH) neurons to identify the target neurons and to
investigate their descending synaptic inputs. Key Results: We
demonstrate that SDH neurons are targeted by descending GABA/glycine
inhibitory inputs from the RVM, although glycinergic inputs predominate.
These SDH neurons had diverse morphological and electrical properties.
This inhibitory synapse was presynaptically suppressed by the kappa
opioid receptor agonist U69593. By contrast, the mu-opioid receptor
agonist DAMGO inhibited only a subset of RVM-SDH synapses, acting both
pre- and postsynaptically, while the delta-opioid receptor agonist
deltorphin II had little effect. Conclusion and Implications: Developing
reliable and effective alternatives to opioid analgesics requires a
detailed, mechanistic understanding of how opioids interact with
nociceptive circuits. This study selectively and systematically
characterises the synaptic connections between RVM projection neurons
and their SDH targets to advance our knowledge of how this descending
projection is organised and modulated. In addition, it improves our
understanding of how opioids alter spinal pathways involved in the
sensations of pain and itch.