Substance P drives endocannabinoid-mediated disinhibition in a midbrain descending analgesic pathway.
Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA(B), mu,delta-opioid, adenosine A(1), and 5HT(1A) receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.
Drew
Geoffrey M
GM
Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. gdrew@med.usyd.edu.au
Lau
Benjamin K
BK
Vaughan
Christopher W
CW
D000344:Afferent Pathways / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D063385:Cannabinoid Receptor Modulators / Q000819:agonists / Q000378:metabolism*; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008526:Medulla Oblongata / Q000166:cytology* / Q000502:physiology; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010487:Periaqueductal Gray / Q000166:cytology* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects* / Q000502:physiology
D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; D018039:Receptors, Tachykinin; D013373:Substance P; D018698:Glutamic Acid