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The Journal of Neuroscience, June 3, 2009, 29(22):7220-7229; doi:10.1523/JNEUROSCI.4362-08.2009

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Behavioral/Systems/Cognitive
Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Geoffrey M. Drew, Benjamin K. Lau, and Christopher W. Vaughan

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

Correspondence should be addressed to Dr. Geoffrey M. Drew, Pain Management Research Institute, Kolling Building, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. Email: gdrew{at}med.usyd.edu.au

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, µ,-opioid, adenosine A₁, 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.

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Received Sept. 12, 2008; revised March 2, 2009; accepted April 29, 2009.

Correspondence should be addressed to Dr. Geoffrey M. Drew, Pain Management Research Institute, Kolling Building, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia. Email: gdrew{at}med.usyd.edu.au

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