Journal of neurophysiology
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Comparative Study
Loss of TRPV1-expressing sensory neurons reduces spinal mu opioid receptors but paradoxically potentiates opioid analgesia.
Systemic administration of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, removes transient receptor potential vanilloid type 1 (TRPV1)-expressing afferent neurons and impairs thermal but not mechanical nociception in adult animals. In this study, we determined how loss of TRPV1-expressing sensory neurons alters the antinociceptive effect of mu opioids and mu opioid receptors in the spinal cord. The effect of morphine and (D-Ala2,N-Me-Phe4,Gly-ol5)-enkephalin (DAMGO) was measured by testing the paw mechanical withdrawal threshold in rats treated with RTX or vehicle. ⋯ The B(MAX) (but not K(D)) of [3H]-DAMGO binding and DAMGO-stimulated [35S]GTPgammaS activity in the dorsal spinal cord were significantly reduced in the RTX group. This study provides novel information that loss of TRPV1 afferent neurons eliminates presynaptic mu opioid receptors present on TRPV1-expressing afferent neurons but paradoxically potentiates the analgesic effect of mu opioid agonists. Mechano-nociception, transmitted through non-TRPV1 sensory neurons, is subject to potent modulation by mu opioid agonists.
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Comparative Study
Inflammation-susceptible Lewis rats show less sensitivity than resistant Fischer rats in the formalin inflammatory pain test and with repeated thermal testing.
Comparisons between Lewis and Fischer inbred strains of rats are used frequently to study the effect of inherent differences in function of the hypothalamic-pituitary-adrenal axis on pain-relevant traits, including differential susceptibility to chronic inflammatory disease and differential responsiveness to analgesic drugs. Increasing use of genetic models including transgenic knockout mice and inbred strains of rodents has raised our awareness of, and the importance of, thorough characterization (or phenotyping) of the strains of rodents being compared. Furthermore, genetic variability in analgesic sensitivity is correlated with, and may be caused by, genetically determined baseline sensitivity. ⋯ Unexpectedly, the more inflammation-susceptible Lewis rats were less sensitive in the formalin inflammatory nociception test, and showed a significant decrease in sensitivity with repeated thermal nociceptive testing, whereas Fischer rats did not. These results affect the interpretation of previously observed results. Further study of the underlying mechanisms and the relevance to differential susceptibility to chronic inflammation is warranted.
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The basolateral amygdala (BLA) is the major amygdaloid nucleus distributed with mu opioid receptors. The afferent input from the BLA to the central nucleus of the amygdala (CeA) is considered important for opioid analgesia. However, little is known about the effect of mu opioids on synaptic transmission in the BLA. ⋯ Bath application of the Kv channel blockers, 4-AP (Kv1.1, 1.2, 1.3, 1.5, 1.6, 3.1, 3.2), alpha-dendrotoxin (Kv1.1, 1.2, 1.6), dendrotoxin-K (Kv1.1), or tityustoxin-Kalpha (Kv1.2) each blocked the inhibitory effect of DAMGO on mIPSCs. Double immunofluorescence labeling showed that some of the immunoreactivities of Kv1.1 and Kv1.2 were colocalized with synaptophysin in the BLA. This study provides new information that activation of presynaptic mu opioid receptors primarily attenuates GABAergic synaptic inputs to CeA-projecting neurons in the BLA through a signaling mechanism involving Kv1.1 and Kv1.2 channels.
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The group I metabotropic glutamate receptor (mGluR) subtype, mGluR1, is highly expressed on the apical dendrites of olfactory bulb mitral cells and thus may be activated by glutamate released from olfactory nerve (ON) terminals. Previous studies have shown that mGluR1 agonists directly excite mitral cells. In the present study, we investigated the involvement of mGluR1 in ON-evoked responses in mitral cells in rat olfactory bulb slices using patch-clamp electrophysiology. ⋯ ON-evoked responses elicited in the presence of THA-TBOA were significantly reduced or completely blocked by LY341495 or LY367385 (100 microM). These results demonstrate that glutamate transporters tightly regulate access of synaptically evoked glutamate from ON terminals to postsynaptic mGluR1s on mitral cell apical dendrites. Taken together with other findings, the present results suggest that mGluR1s may not play a major role in phasic responses to ON input, but instead may play an important role in shaping slow oscillatory activity in mitral cells and/or activity-dependent regulation of plasticity at ON-mitral cell synapses.
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Peripherally delivered opiates attenuate mechanical and thermal hyperalgesia in experimental models of inflammation, suggesting that activation of peripheral opioid receptors decreases the excitability of nociceptors in inflamed tissues. The current study examines the effects of peripheral morphine sulfate on response properties of sensory neurons in healthy and inflamed skin. Afferent units (185) were isolated from tibial nerve of rats using an in vitro glabrous skin-nerve teased-fiber preparation. ⋯ All morphine-sensitive units were nociceptors from inflamed skin with conduction velocities <1.3 m/s. Morphine effects were concentration-dependent and naloxone-sensitive, indicating that the effects were receptor-mediated. These findings provide direct evidence that morphine acts through peripheral opioid receptors to inhibit the activity of cutaneous nociceptors under conditions of inflammation.