Descriptions of proprioceptive-like disorders that persist years after chemotherapy in cancer survivors led us to preclinical investigation of muscle spindles. We find a distinctive defect in mechanosensory encoding by muscle spindles in rats five weeks following treatment with a human-scaled regime of oxaliplatin (OX), a standard treatment in human cancer patients. Specifically, group Ia muscle spindle afferents, though responsive to dynamic muscle stretch, lose the capacity to sustain firing during static stretch [1,2]. Our evidence suggests that defective firing originates in the spindle primary ending, but not as a result of structural degeneration typically held responsible for chronic sensory disorders induced by chemotherapy. An alternate possibility of functional impairment in the generation of receptor and/or action potentials gains support in finding that acute administration of drugs (riluzole and phenytoin) that block slowly inactivating inward Na currents replicate OX-induced firing defects. From these observations, we hypothesize that chronic sensory encoding defects caused by chemotherapy result from channelopathy in the primary sensory endings of muscle spindles. We address our hypothesis using the OX-treatment protocol described above. In attempt to advance translational relevance, we incorporate a rat model of colon cancer that best reproduces features of human colon cancer [3]. Results from treated rats receiving OX treatment were compared with control rats of the same species that were cancer free, untreated, and aged matched. Three kinds of studies were performed on rats in each group. Electrophysiological data were obtained in terminal experiments performed in vivo on isoflurane-anesthetized rats [2]. Action potentials evoked by repeated trials of ramp-hold-release stretch of triceps surae muscles were sampled from single group Ia axons in dorsal roots. The two remaining experiment types were performed on tissues harvested from rats. First, broad transcriptional profiling of fresh dorsal root ganglia was performed using whole genome microarrays (log2 expression). Second, sections of fixed muscles were exposed to monoclonal antibodies and imaged by fluorescent confocal microscopy to reveal relative expression levels (mean fluorescent intensity) and distribution of relevant channels [4]. Spindle afferents sampled from treated rats exhibited the defective firing response profile described above. Means and standard deviations of firing during the hold phase of stretch in OX-treated (n=10 spindles) vs. control (n=11) groups, respectively, were 69±16 pps vs 93±22 pps (p<0.001, ANOVA) for average firing rate and 723±365 ms vs 991±20 ms (p<0.02, ANOVA) for firing duration. Similarity with our earlier findings demonstrates generalizability to both sexes, two rat species, and the presence of cancer. Immunohistochemical examination of muscle spindles began with NaV1.6. Loss of this ion channel and the persistent inward current it generates [5] might have been responsible for the defect in sustained firing as in other neuron types [6]. This explanation was excluded, however, in finding robust labeling for NaV1.6 in the primary sensory terminals and heminodes of muscle spindles comparable to controls. All attempts at replication were successful (26 OX-treated spindles and 32 control spindles, 5 rats each). Consideration of other possible explanations opened us to the complexity of enumerable biophysical mechanisms in muscle spindles that might impair firing. To confront this problem, we turned to transcription profiling, which enabled comprehensive examination of gene expression for all ion channels. Data confirmed equivocal NaV1.6 expression levels between control (6.83±0.32) and treated groups (6.20±0.31 p>0.05, linear fixed effects model (LM)). Among the results, expression of the KCNC3 exhibited distinct downregulation in OX treated relative to control rats, respectively, 6.25±0.14 vs 7.07± 0.06 (p<0.001, LM). Downstream expression of KCNC3’s protein product, Kv3.3, revealed for the first time in control muscle spindles (88.4±53, n=12 spindles) was also decreased (p<0.0001, ANOVA) after OX treatment (41.3±30, n= 9 spindles). Decreased Kv3.3 expression is noteworthy for its capacity to impair high frequency repetitive firing [7]. Moreover, this finding supports our hypothesis and provides the first demonstration of channelopathy in muscle spindle after OX treatment. Results of these ongoing studies suggest new ideas relevant to treating sensory disorders with chemotherapy. Nonetheless, we are far from identifying the molecular mechanism(s) of defective firing. The complexity the muscle spindle’s molecular composition draws attention to the need for comprehensive biophysical models to determine how these ion channels determine transduction and encoding by the primary sensory terminal.