The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli

TY - JOUR

T1 - The impact of bone cancer on the peripheral encoding of mechanical pressure stimuli

AU - Kucharczyk, Mateusz

AU - Chisholm, Kim

AU - Denk, Franziska

AU - Dickenson, Antony

AU - Bannister, Kirsty

AU - McMahon, Stephen

PY - 2020/4/13

Y1 - 2020/4/13

N2 - Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurones innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 post-surgery, designated ‘late’ stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs. Sham-operated, day 14; p < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, DRG in vivo imaging of genetically-encoded calcium indicators and Markov Cluster Analysis were employed to analyse 1748 late-stage CIBP (n=10), and 757 sham-operated (n=9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour: (1) three times as many sensory afferents responded (RM-ANOVA: p < 0.0001 (vs. sham)); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs. sham): p < 0.0001) and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.

AB - Skeletal metastases are frequently accompanied by chronic pain that is mechanoceptive in nature. Mechanistically, cancer-induced bone pain (CIBP) is mediated by peripheral sensory neurones innervating the cancerous site, the cell bodies of which are housed in the dorsal root ganglia (DRG). How these somatosensory neurons encode sensory information in CIBP remains only partly explained. Using a validated rat model, we first confirmed cortical bone destruction in CIBP but not sham-operated rats (day 14 post-surgery, designated ‘late’ stage bone cancer). This occurred with behavioural mechanical hypersensitivity (Kruskal-Wallis H for independent samples; CIBP vs. Sham-operated, day 14; p < 0.0001). Next, hypothesising that the proportion and phenotype of primary afferents would be altered in the disease state, DRG in vivo imaging of genetically-encoded calcium indicators and Markov Cluster Analysis were employed to analyse 1748 late-stage CIBP (n=10), and 757 sham-operated (n=9), neurons. Distinct clusters of responses to peripheral stimuli were revealed. In CIBP rats, upon knee compression of the leg ipsilateral to the tumour: (1) three times as many sensory afferents responded (RM-ANOVA: p < 0.0001 (vs. sham)); (2) there were significantly more small neurons responding (Kruskal-Wallis for independent samples (vs. sham): p < 0.0001) and (3) approximately 13% of traced tibial cavity afferents responded (no difference observed between CIBP and sham-operated animals). We conclude that an increased sensory afferent response is present in CIBP rats and this is likely to reflect afferent recruitment from outside of the bone rather than increased intraosseous afferent activity.

U2 - 10.1097/j.pain.0000000000001880

DO - 10.1097/j.pain.0000000000001880

M3 - Article

SN - 0304-3959

VL - 161

SP - 1894

EP - 1905

JO - Pain

JF - Pain

IS - 8

ER -