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Articles, Neurobiology of Disease

Endocannabinoids in the Brainstem Modulate Dural Trigeminovascular Nociceptive Traffic via CB1 and “Triptan” Receptors: Implications in Migraine

Simon Akerman, Philip R. Holland, Michele P. Lasalandra and Peter J. Goadsby
Journal of Neuroscience 11 September 2013, 33 (37) 14869-14877; DOI: https://doi.org/10.1523/JNEUROSCI.0943-13.2013
Simon Akerman
Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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Philip R. Holland
Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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Michele P. Lasalandra
Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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Peter J. Goadsby
Headache Group, Department of Neurology, University of California, San Francisco, San Francisco, California 94158
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    Figure 1.

    Overview of the experimental setup and neuronal characteristics. A, The basic experimental setup with dural stimulation and recording in the TCC, and modulating the descending contribution of the vlPAG by direct microinjection of compounds. B, The location of all microinjection sites within the vlPAG according to the template from Paxinos and Watson (1998) over an example Pontamine Sky Blue injection site in the vlPAG. All neurons studied were WDR with cutaneous receptive field in at least the first (ophthalmic) division of the trigeminal nerve, but also with corneal and sometimes cutaneous receptive field from the second (mandibular) region of the trigeminal nerve (C). The green shading represents an example of receptive characterization in an animal. D, The location of recording sites in the TCC of nociceptive neurons receiving convergent input from the dura mater and facial receptive field, predominantly in laminae I–II and V. These locations were reconstructed from lesions (●) or from microdrive readings (○) and an original lesion site is included in E. F, An original tracing from a typical unit responding to dural stimulation with latencies in the Aδ-fiber and C-fiber range. 5GN, trigeminal ganglion; Aq, aqueduct; DLPAG, dorsolateral PAG; DMPAG, dorsomedial; V1, first trigeminal (ophthalmic) division; V2, second trigeminal (mandibular) division; V3, third trigeminal (maxillary) division.

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    Figure 2.

    Summary of changes in dural-evoked neuronal firing in the TCC in response to microinjection of the GABAA receptor antagonist bicuculline methiodide into the vlPAG. Dural-evoked Aδ-fiber activity in the TCC is stable and not significant across 30 min of observations with aqueous solution (▵) microinjection in the vlPAG. After microinjection of bicuculline methiodide (●) into the vlPAG there is a significant inhibition of evoked firing in the TCC of (A) Aδ-fiber neurons and (B) basal spontaneous trigeminal tone. C, Original tracing from a dural-evoked Aδ-fiber neuronal response before and after bicuculline that is significantly inhibited. Data are presented as mean ± SEM; *p < 0.05 significance when compared with an average of the three baselines, using Student's paired t test.

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    Figure 3.

    Summary of changes in dural-evoked neuronal firing in the TCC in response to microinjection of a cannabinoid receptor agonist, WIN55,212, into the vlPAG. A, Dural-evoked Aδ-fiber neuronal activity in the TCC was stable after microinjection of vehicle (DMSO) into the vlPAG across 45 min (▿). After microinjection of WIN55,212 (●) into the vlPAG there was significant inhibition of evoked firing in the TCC of neurons with Aδ-fiber latency. These responses were significantly reversed by the specific CB1 receptor antagonist, SR141716 (▵). This was also the case with spontaneous neuronal firing in the TCC (B). WIN55,212 significantly inhibited responses and SR141716 was able to reverse this effect. C, Example of poststimulus histogram (cumulative over 20 dural stimulations) identifying baseline Aδ-fiber responses that are inhibited by WIN55,212 application; a response that is reversed by coapplication with SR141716. In each group poststimulus histograms are taken at the 10 min time point after drug intervention. D, Activation of the facial receptive field with cutaneous V1 pinch and V1 brush or V1 corneal brush was not significant across the treatment groups of baseline: WIN55,212 and WIN55,212 and SR141716. Data are presented as mean ± SEM; *p < 0.05 significance when compared with an average of the three baselines using Student's paired t test.

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    Figure 4.

    Summary of changes in dural-evoked neuronal firing in the TCC in response to microinjection of a specific CB1 receptor agonist (ACPA) and reversal with a 5-HT1B/1D receptor antagonist (GR127935), into the vlPAG. Dural-evoked Aδ-fiber neuronal activity in the TCC was stable after microinjection of vehicle (Tocrisolve) into the vlPAG across 45 min (▵). A, After microinjection of ACPA in the vlPAG there was significant inhibition of evoked firing in the TCC of neurons with Aδ-fiber latency (●). Basal spontaneous trigeminal tone was also significantly reduced (B). C, Responses to ACPA were significantly reversed with prior treatment with either intravenous administration (▿) or microinjection (▵) of GR127925. D, Activation of the facial receptive field with cutaneous V1 pinch and V1 brush or V1 corneal brush was not significant across the treatment groups of baseline, ACPA and ACPA/GR127935 (intravenous; iv) or ACPA/GR137935 (micropipette; mp), respectively. E, Example of poststimulus histogram (cumulative over 20 dural stimulations) identifying baseline Aδ-fiber responses that are inhibited by ACPA application, a response that is reversed by co-microinjection with GR137935. In each group poststimulus histograms are taken at the 15 min time point after drug intervention. Data are presented as mean ± SEM; *p < 0.05 significance when compared with an average of the three baselines or a single baseline for the receptive field, using Student's paired t test.

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The Journal of Neuroscience: 33 (37)
Journal of Neuroscience
Vol. 33, Issue 37
11 Sep 2013
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Endocannabinoids in the Brainstem Modulate Dural Trigeminovascular Nociceptive Traffic via CB1 and “Triptan” Receptors: Implications in Migraine
Simon Akerman, Philip R. Holland, Michele P. Lasalandra, Peter J. Goadsby
Journal of Neuroscience 11 September 2013, 33 (37) 14869-14877; DOI: 10.1523/JNEUROSCI.0943-13.2013

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Endocannabinoids in the Brainstem Modulate Dural Trigeminovascular Nociceptive Traffic via CB1 and “Triptan” Receptors: Implications in Migraine
Simon Akerman, Philip R. Holland, Michele P. Lasalandra, Peter J. Goadsby
Journal of Neuroscience 11 September 2013, 33 (37) 14869-14877; DOI: 10.1523/JNEUROSCI.0943-13.2013
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