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Directed Functional Reinnervation to Curb Nociception and Enable Sensation

ABSTRACT: Peripheral nerve injuries lead to diminished function and pain via nociplastic phenomena. We propose a new strategy called Directed Functional Reinnervation, in which nerves are reassigned to new peripheral targets with the goal of altering circuit function. Here, we redirect pure sensory nerves into skeletal muscle grafts to curb nociplasticity and provide benign or useful inputs for prosthetic applications. Electrophysiological characterization of the functional signaling capabilities demonstrated robust afferent responses to mechanical stimuli. Immunofluorescence staining of the saphenous nerve graft indicated widespread innervation of various synapses within the muscle. With immediate graft placement, the injured nerves’ dorsal root ganglia revealed comparable levels of nociceptive markers to uninjured nerves, suggesting a molecular basis for the prevention of pain sensitization. These findings support the use of skeletal muscle grafts for the alleviation of neuropathic pain and use as a sensory transmitter in conjunction with neural interfaces.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE310748 | GEO | 2025/12/01

REPOSITORIES: GEO

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Project description:Not all patients with nerve injury develop neuropathic pain. The extent of nerve damage and age at the time of injury are two of the few risk factors identified to date. In addition, preclinical studies show that neuropathic pain variance is heritable. To define such factors further, we performed a large-scale gene profiling experiment which plotted global expression changes in the rat dorsal root ganglion in three peripheral neuropathic pain models. This resulted in the discovery that the potassium channel alpha subunit KCNS1, involved in neuronal excitability, is constitutively expressed in sensory neurons and markedly downregulated following nerve injury. KCNS1 was then characterized by an unbiased network analysis as a putative pain gene, a result confirmed by single nucleotide polymorphism association studies in humans. A common amino acid changing allele, the 'valine risk allele', was significantly associated with higher pain scores in five of six independent patient cohorts assayed (total of 1359 subjects). Risk allele prevalence is high, with 18-22% of the population homozygous, and an additional 50% heterozygous. At lower levels of nerve damage (lumbar back pain with disc herniation) association with greater pain outcome in homozygote patients is P = 0.003, increasing to P = 0.0001 for higher levels of nerve injury (limb amputation). The combined P-value for pain association in all six cohorts tested is 1.14 E-08. The risk profile of this marker is additive: two copies confer the most, one intermediate and none the least risk. Relative degrees of enhanced risk vary between cohorts, but for patients with lumbar back pain, they range between 2- and 3-fold. Although work still remains to define the potential role of this protein in the pathogenic process, here we present the KCNS1 allele rs734784 as one of the first prognostic indicators of chronic pain risk. Screening for this allele could help define those individuals prone to a transition to persistent pain, and thus requiring therapeutic strategies or lifestyle changes that minimize nerve injury. Microarrays were run on mRNA extracted from adult rat L4 and L5 DRGs cells after 3,7,21,40 hours after three different sciatic nerve lesions [Spared Nerve Injury (SNI); Chronic Constriction Injury (CCI); Spinal Nerve Ligation (Ch) with Sham controls (SH)].

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Directed Functional Reinnervation to Curb Nociception and Enable Sensation

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