Chronic pain caused by insults to the CNS (central neuropathic pain) is widely assumed to be maintained exclusively by central mechanisms. However, chronic hyperexcitablility occurs in primary nociceptors after spinal cord injury (SCI), suggesting that SCI pain also depends upon continuing activity of peripheral sensory neurons. The present study in rats (Rattus norvegicus) found persistent upregulation after SCI of protein, but not mRNA, for a voltage-gated Na ϩ channel, Nav1.8, that is expressed almost exclusively in primary afferent neurons. Selectively knocking down Nav1.8 after SCI suppressed spontaneous activity in dissociated dorsal root ganglion neurons, reversed hypersensitivity of hindlimb withdrawal reflexes, and reduced ongoing pain assessed by a conditioned place preference test. These results show that activity in primary afferent neurons contributes to ongoing SCI pain.

Octopamine (OA) and tyramine (TA) play important roles in homeostatic mechanisms, behavior, and modulation of neuromuscular junctions in arthropods. However, direct actions of these amines on muscle force production that are distinct from effects at the neuromuscular synapse have not been well studied. We utilize the technical benefits of the Drosophila larval preparation to distinguish the effects of OA and TA on the neuromuscular synapse from their effects on contractility of muscle cells. In contrast to the slight and often insignificant effects of TA, the action of OA was profound across all metrics assessed. We demonstrate that exogenous OA application decreases the input resistance of larval muscle fibers, increases the amplitude of excitatory junction potentials (EJPs), augments contraction force and duration, and at higher concentrations (10(-5) and 10(-4) M) affects muscle cells 12 and 13 more than muscle cells 6 and 7. Similarly, OA increases the force of synaptically driven contractions in a cell-specific manner. Moreover, such augmentation of contractile force persisted during direct muscle depolarization concurrent with synaptic block. OA elicited an even more profound effect on basal tonus. Application of 10(-5) M OA increased synaptically driven contractions by ≈ 1.1 mN but gave rise to a 28-mN increase in basal tonus in the absence of synaptic activation. Augmentation of basal tonus exceeded any physiological stimulation paradigm and can potentially be explained by changes in intramuscular protein mechanics. Thus we provide evidence for independent but complementary effects of OA on chemical synapses and muscle contractility.

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The health care delivery system in the United States, structured to provide single-disease care, presents unique challenges for patients with complex physical and psychiatric comorbidities. Patients in these populations are often referred to multiple specialty clinics, encounter little continuity of care or collaboration among their providers, incur high health care costs, and experience poor treatment outcomes. Given these barriers, questions remain about the extent to which siloed and fragmented care, as opposed to the complex nature of the illnesses themselves, contribute to poor outcomes. If given the opportunity to receive well-integrated, consistent, and personalized care, can patients with historically difficult-to-treat comorbid medical and mental illnesses make progress? This article describes an innovative model of care called functional rehabilitation that is designed to address existing barriers in treatment. The functional rehabilitation program seeks to disrupt the escalating effects of interacting comorbidities by offering highly collaborative treatment from a small team of clinicians, personalized interventions using a shared decision-making framework, multipronged treatment options, colocation in a large hospital system, and significant 1:1 time with patients. The article includes a case example with longitudinal outcome data that illustrates how progress can be made with appropriate programmatic supports. Future research should examine the cost-effectiveness of this model of care.

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