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PURPOSE OF REVIEW: Fractures are painful and disabling injuries that can occur due to trauma, especially when compounded with pathologic conditions, such as osteoporosis in older adults. It is well documented that acute pain management plays an integral role in the treatment of orthopedic patients. There is no current therapy available to completely control post-fracture pain that does not interfere with bone healing or have major adverse effects. In this review, we focus on recent advances in the understanding of pain behaviors post-fracture. RECENT FINDINGS: We review animal models of bone fracture and the assays that have been developed to assess and quantify spontaneous and evoked pain behaviors, including the two most commonly used assays: dynamic weight bearing and von Frey testing to assess withdrawal from a cutaneous (hindpaw) stimulus. Additionally, we discuss the assessment and quantification of fracture pain in the clinical setting, including the use of numeric pain rating scales, satisfaction with pain relief, and other biopsychosocial factor measurements. We review how pain behaviors in animal models and clinical cases can change with the use of current pain management therapies. We conclude by discussing the use of pain behavioral analyses in assessing potential therapeutic treatment options for addressing acute and chronic fracture pain without compromising fracture healing. SUMMARY: There currently is a lack of effective treatment options for fracture pain that reliably relieve pain without potentially interfering with bone healing. Continued development and verification of reliable measurements of fracture pain in both pre-clinical and clinical settings is an essential aspect of continued research into novel analgesic treatments for fracture pain.

Background and Hypothesis: The megakaryocyte (MK) growth factor, thrombopoietin (TPO), improves bone healing in mice, rats, and pigs. Here we explore the role of MK-secreted platelet-derived growth factor-BB (PDGF–BB) in TPO’s mechanism of improving fracture healing. Interestingly, PDGF has neuroprotective effects, and neuronal PDGF receptors (PDGFRs) are primarily stimulated by PDGF–BB. Additionally, fibroblast growth factor 2 (FGF2) is secreted by osteoblasts (OBs), and MKs stimulate OB proliferation; therefore, MKs may regulate FGF2 expression which also promotes nerve regeneration. Importantly, neuropathic pain caused by fractures can be prevented by neuroprotective therapies. We hypothesize that increases in fracture-related neuropathic pain observed with age are due to reductions in: MK-secreted PDGF-BB and MK-stimulated, OBsecreted FGF2. Experimental Design or Project Methods: Dorsal root ganglia (DRG) and MKs from bone marrow and spleens were isolated from 3-4 month-old (young) and 22-24 month-old (old) mice. MKs were also isolated from E13-15 fetal livers of mice and OBs were isolated from the calvaria of neonatal mice. OBs were cultured alone or in the presence of MKs for 4 days. Real-time PCR was completed to examine the expression of PDGF-BB in MKs, FGF2 in OBs, and PDGFR in DRG. Results: Old MKs exhibit a 63% reduction in PDGF–BB expression and old DRG exhibit a 68% reduction in PDGFR expression. OBs cultured with MKs show a 1.78 fold increase in FGF2 expression. Conclusion and Potential Impact: Decreased expression of PDGF-BB in old MKs and PDGFR in old neurons, as well as increased FGF2 expression in OBs cultured with MKs present possible mechanisms for both the reduction in bone healing and increased fracture pain observed with age. TPO improves bone healing and may potentially reduce neuropathic pain directly by increasing MK secreted PDGF-BB and indirectly through MK PDGF-BB stimulating FGF2 secretion from OBs.

Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Nav1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Nav1.6-N1768D). We tested Scn8aN1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8aN1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8aN1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8aN1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8aN1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8aN1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a.

Patients with epileptic encephalopathy have a high risk of sudden unexpected death in epilepsy (SUDEP), an event described as arrhythmia of brain and heart. We investigated the cardiac phenotype of a model of an epileptic encephalopathy caused by mutation of sodium channel SCN8A. We observed that mutant heart cells were hyperexcitable, exhibiting abnormal contraction and action potential wave forms. Mutant mice also had reduced heart rates compared with controls. This difference in heart rate was not observed in isolated hearts, implicating changes in cardiac regulation by the parasympathetic nervous system. When challenged with norepinephrine and caffeine, mutant mice had ventricular arrhythmias. These cardiac and parasympathetic abnormalities are predicted to contribute to the mechanism of SUDEP in patients with SCN8A mutations.