Persistent muscle hyperalgesia after adolescent stress is exacerbated by a mild-nociceptive input in adulthood and is associated with microglia activation.

Non-specific low back pain (LBP) is a major global disease burden and childhood adversity predisposes to its development. The mechanisms are largely unknown. Here, we investigated if adversity in young rats augments mechanical hyperalgesia and how spinal cord microglia contribute to this. Adolescent rats underwent restraint stress, control animals were handled. In adulthood, all rats received two intramuscular injections of NGF/saline or both into the lumbar multifidus muscle. Stress induced in rats at adolescence lowered low back pressure pain threshold (PPT; p = 0.0001) and paw withdrawal threshold (PWT; p = 0.0007). The lowered muscle PPT persisted throughout adulthood (p = 0.012). A subsequent NGF in adulthood lowered only PPT (d = 0.87). Immunohistochemistry revealed changes in microglia morphology: stress followed by NGF induced a significant increase in ameboid state (p < 0.05). Repeated NGF injections without stress showed significantly increased cell size in surveilling and bushy states (p < 0.05). Thus, stress in adolescence induced persistent muscle hyperalgesia that can be enhanced by a mild-nociceptive input. The accompanying morphological changes in microglia differ between priming by adolescent stress and by nociceptive inputs. This novel rodent model shows that adolescent stress is a risk factor for the development of LBP in adulthood and that morphological changes in microglia are signs of spinal mechanisms involved.

TRPM3-mediated dynamic mitochondrial activity in nerve growth factor-induced latent sensitization of chronic low back pain.

ABSTRACT: The transient receptor potential ion channel TRPM3 is highly prevalent on nociceptive dorsal root ganglion (DRG) neurons, but its functions in neuronal plasticity of chronic pain remain obscure. In an animal model of nonspecific low back pain (LBP), latent spinal sensitization known as nociceptive priming is induced by nerve growth factor (NGF) injection. Here, we address the TRPM3-associated molecular basis of NGF-induced latent spinal sensitization at presynaptic level by studying TRPM3-mediated calcium transients in DRG neurons. By investigating TRPM3-expressing HEK cells, we further show the dynamic mitochondrial activity downstream of TRPM3 activation. NGF enhances TRPM3 function, attenuates TRPM3 tachyphylaxis, and slows intracellular calcium clearance; TRPM3 activation triggers more mitochondrial calcium loading than depolarization does, causing a steady-state mitochondrial calcium elevation and a delayed recovery of cytosolic calcium; mitochondrial calcium buffering accounts for approximately 40% of calcium influx subsequent to TRPM3 activation. TRPM3 activation provokes an outbreak of pulsatile superoxide production (mitoflash) that comes in the form of a surge in frequency being tunable. We suggest that mitoflash pulsations downstream of TRPM3 activation might be an early signaling event initiating pain sensitization. Tuning of mitoflash activity would be a novel bottom-up therapeutic strategy for chronic pain conditions such as LBP and beyond.

Analyses of Synthetic N-Acyl Dopamine Derivatives Revealing Different Structural Requirements for Their Anti-inflammatory and Transient-Receptor-Potential-Channel-of-the-Vanilloid-Receptor-Subfamily-Subtype-1 (TRPV1)-Activating Properties.

We studied the chemical entities within N-octanoyl dopamine (NOD) responsible for the activation of transient-receptor-potential channels of the vanilloid-receptor subtype 1 (TRPV1) and inhibition of inflammation. The potency of NOD in activating TRPV1 was significantly higher compared with those of variants in which the ortho-dihydroxy groups were acetylated, one of the hydroxy groups was omitted ( N-octanoyl tyramine), or the ester functionality consisted of a bulky fatty acid ( N-pivaloyl dopamine). Shortening of the amide linker (ΔNOD) slightly increased its potency, which was further increased when the carbonyl and amide groups (ΔNODR) were interchanged. With the exception of ΔNOD, the presence of an intact catechol structure was obligatory for the inhibition of VCAM-1 and the induction of HO-1 expression. Because TRPV1 activation and the inhibition of inflammation by N-acyl dopamines require different structural entities, our findings provide a framework for the rational design of TRPV1 agonists with improved anti-inflammatory properties.