Substance P injections enhance tissue proliferation and regulate sensory nerve ingrowth in rat tendon repair

Abstract

Tendon healing is characterized mostly by slow rehabilitation and, as in tendinopathy, aberrant, protracted sensory nerve ingrowth. This study investigated whether administration of the sensory neuropeptide substance P (SP) could enhance healing and modulate sensory nerve plasticity after Achilles tendon rupture. Fifty-four male Sprague-Dawley rats were allocated to three groups, all receiving six daily injections post-rupture of; (1) SP (10(-6) mol/kg body weight)+endopeptidase inhibitors captopril and thiorphan, (2) captopril/thiorphan only and (3) saline control. At 1, 3 and 6 weeks post-rupture tendon healing was evaluated by assessments of fibroblast proliferation, collagen III-LI (like) occurrence, diameter of newly organized collagen and sensory nerve fiber ingrowth. At 1 week, the SP-treated group exhibited increased occurrence of collagen III-LI (P=0.03) and of organized collagen (P=0.04) compared with control. At 3 weeks, the SP group notably displayed reduced SP-nerve fiber ingrowth (P=0.02), and higher fibroblast density (P=0.004). Both the SP and captopril/thiorphan groups demonstrated increase in collagen fiber organization compared with control (P=0.02 and 0.004, respectively). At 6 weeks, no significant differences were observed between the groups. SP supply in tendon repair promotes early tissue proliferation and regulation of endogenous sensory nerve ingrowth, suggesting implications for novel treatment in tendinopathy.

Tendons: Time to Revisit Inflammation?

“…70 Furthermore, elevated levels of the glutamate receptor, N-methyl-D-aspartate receptor type 1 (NMDAR1) have also been documented in chronic tendinopathy. 71 In this study of patients with symptomatic patellar tendinopathy there was a 9-fold increase of NMDAR1 and a 10-fold increase of glutamate compared with controls.…”

Influence of Comorbidities: Neuropathy, Vasculopathy, and Diabetes on Healing Response Quality

“…Exogenous administration of SP promoted wound and tendon healing. 10,[36][37][38][39] Moreover, inhibition of neutral endopeptidase, which degrades SP, augments epithelialization. 40 Thus, an exogenous SP supply after tendon injury resulted in increased fibroblast number, diameter of the organized collagen, and the amount of collagen III after injury (Fig.…”

Neuronal pathways in tendon healing and tendinopathy - update

“…A second report, originating from the same laboratory utilizing the same model, showed that treatment with SP also increased stress at maximal load and work to maximal load in healing Achilles tendon, although stiffness was not improved compared to controls, and actual failure loads were not reported (185). An interesting observation from one of these studies was that the SP treated group exhibited an accelerated withdrawal of sensory nerve fibers from the injury site during healing (184). This observation may be interesting in the context of human tendinopathy with protracted, pathological sensory nerve fiber ingrowth in the tendon.…”

“…Local injections of SP combined with the neutral endopeptidases thiorphan and captopril were used as a treatment for Achilles tendon rupture in rats (183,184). This resulted in dose dependent increases in fibroblast number at the injury site between 1 and 6 weeks after injury.…”

“…This resulted in dose dependent increases in fibroblast number at the injury site between 1 and 6 weeks after injury. Histological parameters of collagen type III occurrence and collagen organization were enhanced in the SP group as compared to the control group (184). Moreover, collagen fiber orientation and angiogenesis were also improved by SP treatment (183).…”