The Journal of neuroscience : the official journal of the Society for Neuroscience
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Comparative Study
Windup in dorsal horn neurons is modulated by endogenous spinal mu-opioid mechanisms.
The mu-opioid receptor (MOR) plays a critical role in morphine analgesia and nociceptive transmission. However, the physiological roles for endogenous MOR mechanisms in modulating spinal nociceptive transmission, and particularly in the enhanced excitability of spinal nociceptive neurons after repeated noxious inputs, are less well understood. Using a MOR gene knock-out (-/-) approach and an MOR-preferring antagonist, we investigated the roles of endogenous MOR mechanisms in processing of acute noxious input and in neuronal sensitization during windup-inducing stimuli in wide dynamic range (WDR) neurons. ⋯ A trend toward facilitation of windup was also observed during 1.0 Hz stimulation after naloxone treatment. These results suggest that endogenous MOR mechanisms are not essential in the processing of acute noxious mechanical and electrical stimuli by WDR neurons. However, MORs may play an important role in endogenous inhibitory mechanisms that regulate the development of spinal neuronal sensitization.
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The transient receptor potential vanilloid 4 (TRPV4) is a primary afferent transducer that plays a crucial role in neuropathic hyperalgesia for osmotic and mechanical stimuli, as well as in inflammatory mediator-induced hyperalgesia for osmotic stimuli. In view of the clinical importance of mechanical hyperalgesia in inflammatory states, the present study investigated the role of TRPV4 in mechanical hyperalgesia induced by inflammatory mediators and the second-messenger pathways involved. Intradermal injection of either the inflammogen carrageenan or a soup of inflammatory mediators enhanced the nocifensive paw-withdrawal reflex elicited by hypotonic or mechanical stimuli in rat. ⋯ Additional behavioral observations suggested that multiple mediators are necessary to achieve sufficient activation of the cAMP pathway to engage the TRPV4-dependent mechanism of hyperalgesia. In addition, direct activation of protein kinase A or protein kinase C epsilon, two pathways that mediate inflammation-induced mechanical hyperalgesia, also induced hyperalgesia for both hypotonic and mechanical stimuli that was decreased by TRPV4 antisense and absent in TRPV4(-/-) mice. We conclude that TRPV4 plays a crucial role in the mechanical hyperalgesia that is generated by the concerted action of inflammatory mediators present in inflamed tissues.
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A fundamental objective of anesthesia research is to identify the receptors and brain regions that mediate the various behavioral components of the anesthetic state, including amnesia, immobility, and unconsciousness. Using complementary in vivo and in vitro approaches, we found that GABAA receptors that contain the alpha5 subunit (alpha5GABAARs) play a critical role in amnesia caused by the prototypic intravenous anesthetic etomidate. Whole-cell recordings from hippocampal pyramidal neurons showed that etomidate markedly increased a tonic inhibitory conductance generated by alpha5GABAARs, whereas synaptic transmission was only slightly enhanced. ⋯ The alpha5-/- mice did not exhibit a generalized resistance to etomidate, in that the sedative-hypnotic effects measured with the rotarod, loss of righting reflex, and spontaneous motor activity were similar in WT and alpha5-/- mice. Deletion of the alpha5 subunit of the GABAARs reduced the amnestic but not the sedative-hypnotic properties of etomidate. Thus, the amnestic and sedative-hypnotic properties of etomidate can be dissociated on the basis of GABAAR subtype pharmacology.