Pain
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Recently, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a newly designed μ-opioid receptor (MOR) agonist with a low pKa, has been shown to produce injury-restricted analgesia in models of inflammatory and postoperative pain, without exhibiting typical opioid side effects. Here, we investigated MOR binding of NFEPP in brain and dorsal root ganglia, pH in injured tissues, and the analgesic efficacy of NFEPP compared with fentanyl in a chronic constriction injury model of neuropathic pain, and in the acetic acid-induced abdominal writhing assay in rats. Binding experiments revealed significantly lower affinity of NFEPP compared with fentanyl at pH 7.4. ⋯ Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid-induced abdominal constrictions. In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity. Our results indicate that NFEPP exerts peripheral opioid receptor-mediated analgesia exclusively in damaged tissue in models of neuropathic and abdominal pain.
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The dorsal horn of the spinal cord (laminae I-VI) processes diverse modalities of nociceptive and nonnociceptive sensory information. Antenna-type neurons with cell bodies located in lamina III and large dendritic trees extending from the superficial lamina I to deep lamina IV are best shaped for the integration of a wide variety of inputs arising from primary afferent fibers and intrinsic spinal circuitries. Although the somatodendritic morphology, the hallmark of antenna neurons, has been well studied, little is still known about the axon structure and basic physiological properties of these cells. ⋯ The neurons received monosynaptic inputs from the low-threshold Aβ afferents, Aδ afferents, as well as from the high-threshold Aδ, and C afferents. When selectively activated, C-fiber-driven monosynaptic and polysynaptic excitatory postsynaptic potentials were sufficiently strong to evoke firing in the neurons. Thus, lamina III antenna neurons integrate low-threshold and nociceptive high-threshold primary afferent inputs and can function as wide dynamic range neurons able to directly connect deep dorsal horn with the major nociceptive projection area lamina I.
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We have previously demonstrated that lysophosphatidic acid (LPA) plays key roles in the initial mechanisms for neuropathic pain (NeuP) development. Here, we examined whether LPA receptor mechanisms and LPA production are related to the glial activation at a late stage after partial sciatic nerve ligation (pSNL) by use of microglial inhibitor, Mac1-saporin or astrocyte inhibitor, and L-α-aminoadipate (L-AA). Although single intrathecal injection of LPA1/3 antagonist, Ki-16425 did not affect the pain threshold at day 7 after the spinal cord injury, repeated treatments of each compound gradually reversed the basal pain threshold to the control level. ⋯ The involvement of LPA receptors in astrocyte activation in vivo was evidenced by the findings that Ki-16425 treatments abolished the upregulation of CXCL1 in activated astrocytes in the spinal dorsal horn of mice at day 14 after the pSNL, and that Ki-16425 reversed the LPA-induced upregulation of several chemokine gene expressions in primary cultured astrocytes. Finally, we found that significant hyperalgesia was observed with intrathecal administration of primary cultured astrocytes, which had been stimulated by LPA in a Ki-16425-reversible manner. All these findings suggest that LPA production and LPA1/3 receptor activation through differential glial mechanisms play key roles in the maintenance as well as initiation mechanisms in NeuP.
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Movement is changed in pain, but the mechanisms remain unclear. Key questions are unresolved such as whether activation can be inhomogeneously distributed within a muscle in a manner that is specific to the location of noxious input. This study addressed this question using high-density electromyography (EMG) to study regional redistribution of muscle activation within the vasti muscles and changes in knee extension force direction in response to noxious stimulation applied to muscular and nonmuscular tissues around the knee. ⋯ Preferential reduction of activation of the distal region of vastus medialis was observed when distal vastus medialis (P < 0.001) or vastus lateralis (P < 0.05) was injected. Both adaptations persisted after pain resolution. These results support the hypothesis that specific adaptation depends on the location of a noxious stimulus and imply that recovery of pain is not necessarily concomitant with return of the EMG to prepain patterns.
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The lionfish (Pterois volitans) is a venomous invasive species found in the Caribbean and Northwestern Atlantic. It poses a growing health problem because of the increase in frequency of painful stings, for which no treatment or antidote exists, and the long-term disability caused by the pain. Understanding the venom's algogenic properties can help identify better treatment for these envenomations. ⋯ The algogenic substance(s) are heat-labile peptides that cause neurogenic inflammation at the site of injection and induction of Fos and microglia activation in the superficial layers of the dorsal horn. Finally, calcium imaging and electrophysiology experiments show that the venom acts predominantly on nonpeptidergic, TRPV1-negative, nociceptors, a subset of neurons implicated in sensing mechanical pain. These data provide the first characterization of the pain and inflammation caused by lionfish venom, as well as the first insight into its possible cellular mechanism of action.