title: Functional Organization of Cutaneous and Muscle Afferent Synapses onto Immature Spinal Lamina I Projection Neurons.
abstract: It is well established that sensory afferents innervating muscle are more effective at inducing hyperexcitability within spinal cord circuits compared with skin afferents, which likely contributes to the higher prevalence of chronic musculoskeletal pain compared with pain of cutaneous origin. However, the mechanisms underlying these differences in central nociceptive signaling remain incompletely understood, as nothing is known about how superficial dorsal horn neurons process sensory input from muscle versus skin at the synaptic level. Using a novelex vivospinal cord preparation, here we identify the functional organization of muscle and cutaneous afferent synapses onto immature rat lamina I spino-parabrachial neurons, which serve as a major source of nociceptive transmission to the brain. Stimulation of the gastrocnemius nerve and sural nerve revealed significant convergence of muscle and cutaneous afferent synaptic input onto individual projection neurons. Muscle afferents displayed a higher probability of glutamate release, although short-term synaptic plasticity was similar between the groups. Importantly, muscle afferent synapses exhibited greater relative expression of Ca2+-permeable AMPARs compared with cutaneous inputs. In addition, the prevalence and magnitude of spike timing-dependent long-term potentiation were significantly higher at muscle afferent synapses, where it required Ca2+-permeable AMPAR activation. Collectively, these results provide the first evidence for afferent-specific properties of glutamatergic transmission within the superficial dorsal horn. A larger propensity for activity-dependent strengthening at muscle afferent synapses onto developing spinal projection neurons could contribute to the enhanced ability of these sensory inputs to sensitize central nociceptive networks and thereby evoke persistent pain in children following injury.SIGNIFICANCE STATEMENTThe neurobiological mechanisms underlying the high prevalence of chronic musculoskeletal pain remain poorly understood, in part because little is known about why sensory neurons innervating muscle appear more capable of sensitizing nociceptive pathways in the CNS compared with skin afferents. The present study identifies, for the first time, the functional properties of muscle and cutaneous afferent synapses onto immature lamina I projection neurons, which convey nociceptive information to the brain. Despite many similarities, an enhanced relative expression of Ca2+-permeable AMPA receptors at muscle afferent synapses drives greater LTP following repetitive stimulation. A preferential ability of the dorsal horn synaptic network to amplify nociceptive input arising from muscle is predicted to favor the generation of musculoskeletal pain following injury.
authors.affiliation: Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Pain Research Center, Department of Anesthesiology, University of Cincinnati Medical Center, Cincinnati, Ohio 45267 mark.baccei@uc.edu.
authors.forename: Mark L
authors.identifier: 0000-0003-3337-7480
authors.initials: ML
authors.lastname: Baccei
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D008297:Male; D018482:Muscle, Skeletal / Q000294:innervation* / Q000502:physiology*; D009475:Neurons, Afferent / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000294:innervation*; D012879:Skin Physiological Phenomena; D066148:Spinal Cord Dorsal Horn / Q000166:cytology / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D055366:Synaptic Potentials / Q000502:physiology
keywords: dorsal horn; glutamate; pain; patch clamp; primary afferent; synaptic plasticity