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Rheumatic diseases are often associated to debilitating chronic joint pain, which remains difficult to treat and requires new therapeutic strategies. Here, we describe increased content of lysophosphatidyl-choline (LPC) 16:0 in the knee synovial fluids of two independent cohorts of patients with painful joint diseases. If LPC16:0 levels correlated with pain in patients with osteoarthritis (OA), they do not appear to be the hallmark of a particular joint disease. We found that intra-articular injections of LPC16:0 in mouse produce chronic pain and anxiety-like behaviors in both males and females with no apparent inflammation, peripheral nerve sprouting and damage, nor bone alterations. LPC16:0-induced persistent pain state is dependent on peripheral Acid-Sensing Ion Channel 3 (ASIC3), ultimately leading to central sensitization. LPC16:0 and ASIC3 thus appear as key players of chronic joint pain with potential implications in OA and possibly across others rheumatic diseases.

Introduction Within superficial trigeminal nucleus caudalis (Sp5C) (laminae I/II), meningeal primary afferents project exclusively to lamina I, whereas nociceptive cutaneous ones distribute in both lamina I and outer lamina II. Whether such a relative absence of meningeal inputs to lamina II represents a fundamental difference from cutaneous pathways in the central processing of sensory information is still unknown. Methods We recorded extracellular field potentials in the superficial Sp5C of anesthetised rats evoked by electrically stimulating the dura mater, to selectively assess the synaptic transmission between meningeal primary afferents and second-order Sp5C neurons, the first synapse in trigeminovascular pathways. We tested the effect of systemic morphine and local glycinergic and GABAAergic disinhibition. Results Meningeal stimulation evokes two negative field potentials in superficial Sp5C. The conduction velocities of the activated primary afferents are within the Aδ- and C-fibre ranges. Systemic morphine specifically suppresses meningeal C-fibre-evoked field potentials, and this effect is reversed by systemic naloxone. Segmental glycinergic or GABAAergic disinhibition strongly potentiates meningeal C-fibre-evoked field potentials but not Aδ-fibre ones. Interestingly, the same segmental disinhibition conversely potentiates cutaneous Aδ-fibre-evoked field potentials and suppresses C-fibre ones. Conclusion These findings reveal that the different anatomical organization of meningeal and cutaneous inputs into superficial Sp5C is associated with a different central processing of meningeal and cutaneous pain information within Sp5C. Moreover, they suggest that the potentiation upon local disinhibition of the first synapse in trigeminovascular pathways may contribute to the generation of headache pain.

International audience; Bone cancer pain is a common and disruptive symptom in cancer patients. In cancer pain animal models, massive reactive astrogliosis in the dorsal horn of the spinal cord has been reported. Because astrocytes may behave as driving partners for pathological pain, we investigated the temporal development of pain behavior and reactive astrogliosis in a rat bone cancer pain model induced by injecting MRMT-1 rat mammary gland carcinoma cells into the tibia. Along with the development of bone lesions, a gradual mechanical and thermal allodynia and hyperalgesia as well as a reduced use of the affected limb developed in bone cancer-bearing animals, but not in sham-treated animals. Dorsal horn Fos expression after nonpainful palpation of the injected limb was also increased in bone cancer-bearing animals. However, at any time during the evolution of tumor, there was no increase in glial fibrillary acidic protein (GFAP) immunoreactivity in the dorsal horn. Further analysis at 21days after injection of the tumor showed no increase in GFAP and interleukin (IL) 1β transcripts, number of superficial dorsal horn S100β protein immunoreactive astrocytes, or immunoreactivity for microglial markers (OX-42 and Iba-1). In contrast, all these parameters were increased in the dorsal horn of rats 2weeks after sciatic nerve ligation. This suggests that in some cases, bone cancer pain may not be correlated with spinal overexpression of reactive glia markers, whereas neuropathic pain is. Glia may thus play different roles in the development and maintenance of chronic pain in these 2 situations.

Specialized primary afferents, although they terminate in different laminae within the dorsal horn (DH), are known to interact through local circuit excitatory and inhibitory neurons. That a loss of segmental inhibition probably contributes to persistent pain hypersensitivity during chronic pain raises the question as to how disinhibition-induced changes in cross-modal interactions account for chronic pain symptoms. We sought to characterize how pharmacological blockade of glycine and gamma-aminobutyric acid (GABA) receptors modifies synaptic transmission between primary afferent fibers and second-order neurons by recording field potentials in the superficial medullary dorsal horn (MDH) of anesthetized rats. Transcutaneous electrical stimulation evokes three negative field potentials elicited by, from earliest to latest, Aβ-, Aδ- and C-fiber primary afferents. Blocking segmental glycine and/or GABA(A) receptors, with strychnine and bicuculline, respectively, strongly facilitates Aβ- and Aδ-fiber-evoked polysynaptic field potentials but, conversely, inhibits, or even abolishes, the whole C-fiber field potential. Blocking segmental GABA(B) receptors, with phaclofen, reverses such suppression of C-fiber field potentials. Interestingly, it also potentiates C-fiber field potentials under control conditions. Finally, activation of segmental GABA(B) receptors, with baclofen, preferentially inhibits C-fiber field potentials. Our results suggest that activation of A-fiber primary afferents inhibits C-fiber inputs to the MDH by the way of polysynaptic excitatory pathways, last-order GABAergic interneurons and presynaptic GABA(B) receptors on C-fiber primary afferents. Under physiological conditions, activation of such local DH circuits is closely controlled by segmental inhibition but it might contribute to paradoxically reduced pain hypersensitivity under pathological disinhibition.