Background & Aims

Millions of patients undergo surgery each year with many developing post-surgical pain. A common yet disturbing symptom is when tactile stimuli such as clothing close to the surgical site elicits pain sensation. Tactile-evoked pain involves cross-talk between tactile inputs and pain circuits in the spinal cord (Peirs et al., 2020). However, the tactile inputs that drive post-surgical tactile-evoked pain have not been defined. This study aimed to characterise skin innervation and tactile-evoked pain behaviours in a rat model of post-surgical pain (Brennan et al., 1996). Initial studies revealed the development of novel tactile corpuscles around the incision site, with a time course that matched tactile-evoked pain behaviour. Given tactile corpuscles require BDNF-TrkB signalling in order to form (Meltzer et al., 2021), the requirement of BDNF-TrkB signalling for this novel tactile innervation and tactile allodynia was investigated.

Methods

Hindpaw skin-muscle heel incision was performed under isoflurane anaesthesia in adult Sprague-Dawley rats. Immunostaining: Biopsies were collected (post-surgical day (PSD)s 1,2,3,& 7) from incision heel, contralateral heel and control pad. Tissue was sectioned and immunostained for PGP9.5 to quantify nociceptive innervation (intra-epidermal nerve fibres); NF200 and S100 to quantify tactile innervation; DAPI to quantify epidermal thickness; and Collagen IV to delineate the dermal-epidermal junction. Behaviour: Rats underwent behavioural assessment of tactile sensitivity (paintbrush stroking) (adapted from Duan et al. 2014) and thermal sensitivity (Hargreaves) at baseline and at PSD 1,3,& 7. BDNF-TrkB requirement was explored using a TrkB-Fc chimera: 100ng/50ul of TrkB-Fc dissolved in PBS was injected subcutaneously around the incision following surgery and on PSD2. Behaviour and immunostaining on PSD3 was compared between TrkB-Fc, vehicle and no injection groups. All groups n= or > 6.

Results

In the incision tissue surround, there is a significant increase in epidermal thickness accompanied by a reduction in nociceptive innervation. There is a striking change in skin structure with the development of dermal protrusions, reminiscent of dermal papillae, oriented towards the incision site. These dermal papillae are innervated with putative tactile corpuscles with a time course matching tactile-evoked pain behaviours. Increased epidermal BDNF immunostaining intensity was observed in the incision site surround. TrkB-Fc administration reduced tactile-evoked pain behaviours, whilst thermal hyperalgesia was unaltered. TrkB-Fc administration also reduced the size of the tactile corpuscles (S100+ bulb area), but did not alter gross wound area, BDNF immunostaining intensity, intra-epidermal nerve fibre density or tactile corpuscle density.

Conclusions

In the rat hindpaw surgical incision model, the incision site surround has reduced nociceptive innervation but novel innervation by putative tactile corpuscles. The novel innervation by putative tactile corpuscles involves a BDNF-TrkB dependent mechanism that contributes to post-surgical tactile-evoked pain.

References

• Peirs et al., 2020. Recent advances in our understanding of the organization of dorsal horn neuron populations and their contribution to cutaneous mechanical allodynia. J Neural Transm (Vienna).
• Brennan et al., 1996. Characterization of a rat model of incisional pain. Pain.
• Duan et al., 2014. Identification of spinal circuits transmitting and gating mechanical pain. Cell.
• Meltzer et al., 2021. The cellular and molecular basis of somatosensory neuron development. Neuron.

Presenting Author

Ying Sze

Poster Authors

Ying Sze

PhD

University of Edinburgh

Lead Author

Kirsten Wilson

University of Edinburgh

Lead Author

Carole Torsney

Centre for Discovery Brain Sciences

Lead Author

Katarzyna Mazur

Centre for Discovery Brain Sciences, University of Edinburgh

Lead Author

Chunyi Zhu

University of Edinburgh

Lead Author

Anna Regan

University of Edinburgh

Lead Author

Atanaska Velichkova

University of Edinburgh

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Post-surgical/Post-traumatic Chronic Pain