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 lacking. 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.

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.

Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn (SDH) of the spinal cord that are involved in the modulation of acute nociception and the development of chronic pain and itch. This projection is believed to be primarily inhibitory but the relative contribution of GABA and glycine transmission is unknown and there is limited knowledge about the spinal targets of RVM-SDH projections. We address this using ex vivo optogenetic stimulation of RVM descending fibres in conjunction with whole-cell patch-clamp recordings from SDH neurons in spinal cord slices. We demonstrate that SDH target neurons have diverse morphological and electrical properties and that RVM inputs onto these neurons are mediated by two inhibitory neurotransmitters, GABA and glycine. Interestingly, one type of SDH target neuron received glycine dominant inputs. These findings confirm that descending RVM synaptic inputs to spinal pain pathway neurons are largely inhibitory show that they involve not only GABAergic but also glycinergic systems. The present study records descending RVM inputs to SDH in isolation and provides mechanistic information about the neurotransmitter systems this input uses to control spinal pain/itch pathways.