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 are 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.