Abstract
Motor impairment is one of the serious side-effects of morphine, which is an exogenous agonist of the μ-opioid receptor (MOR) as well as a widely used analgesic drug in clinical practice for chronic pain treatment. Endomorphins (EMs, including EM-1 and EM-2), the most effective and specific endogenous agonists of the MOR, exert more potent analgesia in acute and neuropathic pain than other opiates, such as morphine. Although EMs had fewer side-effects comparing to other opiates, motor impairment was still one unwanted reaction which limited its clinical application. In order to prevent and treat the motor impairment, it is critical to reveal the neural mechanisms underlying such locomotion disorder. The purpose of the present study was to reveal the neural mechanisms underlying the effects of EM-2 on the activity of motoneurons in the spinal ventral horn. First, we examine the distribution of EM-2-immunoreactive (IR) primary afferent fibers and their synaptic connections with the motoneurons innervating the skeletal muscles of the lower limb revealed by sciatic nerve retrograde tracing. The results showed that EM-2-IR fibers and terminals were sparsely observed in lamina IX and they formed symmetric synaptic connections with the motoneurons within lamina IX of the spinal ventral horn. Then, whole-cell patch-clamp technique was used to observe the effects of EM-2 on the spontaneous excitatory postsynaptic current (sEPSC) of motoneurons in lamina IX. The results showed that EM-2 could decrease both the frequency and amplitude of the sEPSC of the motoneurons in lamina IX, which was reversed by the MOR antagonist CTOP. These results indicate that EM-2-IR fibers originated from primary afferent fibers form symmetric synaptic connections with motoneurons innervating skeletal muscles of the lower limbs in lamina IX of the spinal ventral horn and EM-2 might exert inhibitory effects on the activities of these motoneurons through both presynaptic and postsynaptic mechanisms.
Highlights
Morphine is the most effective analgesic in clinical treatment, especially in postoperative pain and neuropathic pain (Corbett et al, 2006)
In order to examine the distribution of EM-2-like IR fibers and terminals and the connections between EM-2-IR fibers and motoneurons in lamina IX of the spinal ventral horn, a double-labeling method combining TMR-DA retrograde tracing with immunofluorescence histochemical staining for EM-2 was applied
After injection of TMR-DA into the peripheral portion of the sciatic nerve at the middle of the thigh, some large neuronal cell bodies within lamina IX innervating the skeletal muscles of the lower limb through sciatic nerve were labeled by TMR-DA (Figures 1A,C)
Summary
Morphine is the most effective analgesic in clinical treatment, especially in postoperative pain and neuropathic pain (Corbett et al, 2006). Tyr-D-Ala-Gly-N-Met-Phe-Gly-ol (DAMGO), an artificially synthesized agonist of the MOR, hyperpolarizes lamina IX motoneurons in the spinal ventral horn by G protein-mediated activation of potassium channels after activation of MORs. DAMGO decreased the frequency of spontaneous excitatory and inhibitory postsynaptic currents to reduce both excitatory and inhibitory transmitter release. DAMGO decreased the frequency of spontaneous excitatory and inhibitory postsynaptic currents to reduce both excitatory and inhibitory transmitter release They just recorded lamina IX neurons (not identified spinal motoneurons), and failed to exclude some spinal interneurons (Honda et al, 2012). All of these results suggested that EM-2 might play a crucial role in locomotion regulation at the spinal cord level. Immunoelectron microscope technique was to show the synaptic connections between EM-2 terminals and motoneurons, providing direct morphological evidence for these electrophysiological results
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