Mol Pain
-
Disinhibition of neurons in the superficial spinal dorsal horn, via microglia - neuron signaling leading to disruption of chloride homeostasis, is a potential cellular substrate for neuropathic pain. But, a central unresolved question is whether this disinhibition can transform the activity and responses of spinal nociceptive output neurons to account for the symptoms of neuropathic pain. ⋯ The transformation of discharge activity and sensory specificity provides an aberrant signal in a primarily nociceptive ascending pathway that may serve as a basis for the symptoms of neuropathic pain.
-
Endothelin-1 (ET-1) both stimulates nociceptors and sensitizes them to noxious stimuli, an effect probably mediated by the ETA receptor (ETAR) expressed in sensory neurons. The cellular mechanisms of this ET-1-mediated effect are only poorly understood. TRPV1, the heat-, pH- and capsaicin-sensitive cation channel already known to be modulated by a number of cellular mediators released in response to noxious stimuli and during inflammation, is a potential target for the action of ET-1. ⋯ We conclude that ET-1 potentiates TRPV1 by a PKC-dependent mechanism and that this could play a major role in the algogenic and hyperalgesic effects of ET-1 described in previous studies.
-
Inflammatory mediators can directly sensitize primary afferent nociceptors to mechanical and osmotic stimuli. Sensitized nociceptors have a lowered threshold of activation and increased spontaneous activity, which result in symptoms of hyperalgesia and pain, respectively. The transient receptor potential vanilloid 4 (TRPV4) ligand-gated ion channel has been implicated in the hyperalgesia for mechanical and osmotic stimuli associated with inflammatory states. ⋯ Following the injection of the soup, the percentage of C-fibers responding to a hypotonic stimulus and the magnitude of the response was significantly greater in TRPV4+/+ mice compared to TRPV4-/- mice. Moreover, in response to simplified inflammatory soup only C-fibers from TRPV4+/+ mice exhibited increased spontaneous activity and decreased mechanical threshold. These marked impairments in the response of C-fibers in TRPV4-/- mice demonstrate the importance of TRPV4 in nociceptor sensitization; we suggest that TRPV4, as TRPV1, underlies the nociceptive effects of multiple inflammatory mediators on primary afferent.
-
Neuronal nitric oxide synthase (nNOS) is a key enzyme for nitric oxide production in neuronal tissues and contributes to the spinal central sensitization in inflammatory pain. However, the role of nNOS in neuropathic pain remains unclear. The present study combined a genetic strategy with a pharmacologic approach to examine the effects of genetic knockout and pharmacologic inhibition of nNOS on neuropathic pain induced by unilateral fifth lumbar spinal nerve injury in mice. ⋯ Western blot analysis showed that the expression of nNOS protein was significantly increased in ipsilateral L5 dorsal root ganglion but not in ipsilateral L5 lumbar spinal cord on day 7 post-nerve injury. The expression of inducible NOS and endothelial NOS proteins was not markedly altered after nerve injury in either the dorsal root ganglion or spinal cord. Our findings suggest that nNOS, especially in the dorsal root ganglion, may participate in the development and/or maintenance of mechanical hypersensitivity after nerve injury.
-
While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. ⋯ In contrast, alcohol but not ddC caused enhanced response to mechanical stimulation (i.e., decrease in threshold and increase in response to sustained threshold and supra-threshold stimulation) and changes in pattern of evoked activity (interspike interval and action potential variability analyses). These marked differences in primary afferent nociceptor function, in two different forms of neuropathy that produce mechanical hyperalgesia of similar magnitude, suggest that optimal treatment of neuropathic pain may differ depending on the nature of the causative insult to the peripheral nervous system, and emphasize the value of studying co-morbid conditions that produce painful peripheral neuropathy by different mechanisms.