Endocannabinoids: Molecular, Pharmacological, Behavioral and Clinical Features

The Role of Endocannabinoids and Arachidonic Acid Metabolites in Emesis

Author(s): Nissar A. Darmani and Seetha Chebolu

Pp: 25-59 (35)

DOI: 10.2174/9781608050284113010007

* (Excluding Mailing and Handling)

Abstract

Research in the last decade has well established that Δ9-THC and related synthetic direct-acting cannabinoid CB1/2 receptor agonists (such as WIN55,212-2, CP55,940) possess broad-spectrum antiemetic efficacy against diverse emetogens via activation of CB1 receptors. We now extend the antiemetic efficacy of these CB1/2 agonists against 20-hydroxyPGE2 and arachidonoyl-2-chloroethylamide (ACEA). Increasing evidence in more recent years also suggests that chronic use of large doses of Δ9-THC in humans can induce intractable vomiting referred to as the cannabinoid hyperemesis syndrome. This chapter discusses the antiemetic/proemetic potential of endocannabinoids such as anandamide, virodhamine, NADA and 2-AG as well as that of synthetic indirectacting cannabimimetic agents that increase endogenous endocannabinoid tissue levels either by inhibiting their metabolism {such as FAAH and MAGL inhibitors (e.g. AA-5- HT/URB597 and JZL184, respectively)} or by blocking their reuptake (e.g. OMDM1, VDM11, AM404). To date published findings indicate that exogenous administration of either 2-AG or anandamide can lead to both antiemetic and proemetic effects depending upon the laboratory conditions used and/or the emetic models utilized. Furthermore, lack of full dose-response studies in most emesis models further confounds a firm conclusion. Likewise, available data indicate that the well-studied FAAH inhibitor URB597 and the above reuptake blockers can prevent vomiting induced by some but not all tested emetogens, and at large doses they can be emetic by themselves. It appears that while the antiemetic efficacy of exogenously-administered endocannabinoids (as well as that of drugs that increase their endogenous levels) is due to activation of CB1- or CB1/TRPV1- receptors, e.g. 2-AG or anandamide, respectively, their emetic potential reside in their tendency to be rapidly metabolized to the proemetic agent arachidonic acid and its downstream emetic metabolites such as prostaglandins (e.g. PGE2, 20-hydroxyPGE2 and PGF2α), leukotrienes (e.g. LTC4 and LTD4) and/or 20-HETE. In fact some analogs of anandamide such as ACEA (a selective CB1 agonist) that are more rapidly metabolized are proemetic, while its more stable congeners (methanandamide or ACPA) lack emetic activity. Thus, exogenously-administered endocannabinoids and drugs that enhance their tissue levels can be antiemetic under certain conditions but unlike Δ9-THC they generally lack broad-spectrum antiemetic efficacy.


Keywords: Emesis, cannabinoids, Δ99-THC, virodhamine, ACEA, CP55, 940, WIN55, 212-2, Prostaglandin F2αProstaglandin E2, 20-hydroxy- prostaglandin E2, Prostaglandin G2, 20-HETE, Area postrema, nucleus tractus solitarius.

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      • 11. app/Models/ContentAccess.php:647
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      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1518
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Trial Access" as access_base_text, CASE j.type WHEN 111 THEN true ELSE false END as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_trail` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59068240 and j.to_ip >=59068240 )) and ((j.from_date <= 1740515613 and j.to_date >= 1740515613 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 5540) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Subscribed" as access_base_text, false as terms_popup, "S" as content_download_type, null as restricted_user_access_key, null as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_corporate` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59068240 and j.to_ip >=59068240 )) and ((j.from_date <= 1740515613 and j.to_date >= 1740515613 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 5540) union (select j.user_access_id,j.volume_id,j.user_id,j.from_ip,j.to_ip,j.type,j.track,"Token Based Access" as access_base_text, false as terms_popup, "R" as content_download_type, j.uc_id as restricted_user_access_key, "v" as restricted_user_access_type, CASE j.track WHEN 0 THEN false ELSE true END as tracksAccessByVolume,"chapter" as access_level, j.chapter_id from `user_access_chapter_token` as `j` inner join `user_access_info` as `info` on `j`.`user_access_id` = `info`.`user_access_id` where ((j.from_ip <= 59068240 and j.to_ip >=59068240 )) and ((j.from_date <= 1740515613 and j.to_date >= 1740515613 and j.perpetual= 0) or (j.from_date is null and j.to_date is null and j.perpetual= 1)) and j.chapter_id = 5540)
      730μsalphaeurekaselec_live_10_06_2022UserAccess.php#1266
      Backtrace
      • 13. app/Models/UserAccess/UserAccess.php:1266
      • 14. app/Http/Controllers/ChapterController.php:1549
      • 15. vendor/laravel/framework/src/Illuminate/Routing/Controller.php:54
      • 16. vendor/laravel/framework/src/Illuminate/Routing/ControllerDispatcher.php:43
      • 17. vendor/laravel/framework/src/Illuminate/Routing/Route.php:260
    • select b.banner_link, b.banner_name, b.banner_script, b.banner_remarks, b.banner_file_name, b.banner_placement, bd.content_type, bd.content_id from `tbl_banner` as `b` inner join `tbl_banner_detail` as `bd` on `bd`.`banner_id` = `b`.`banner_id` inner join `users` as `u` on `u`.`id` = `b`.`updated_by` where `b`.`banner_ebook` = 1 and `bd`.`content_type` = 'B' and `bd`.`content_id` = 1311 and `b`.`banner_from_date` <= 1740515613 and `b`.`banner_to_date` >= 1740515613 and `b`.`banner_status` = 'A' order by `b`.`banner_id` desc
      1.19msalphaeurekaselec_live_10_06_2022Banner.php#95
      Bindings
      • 0: 1
      • 1: B
      • 2: 1311
      • 3: 1740515613
      • 4: 1740515613
      • 5: A
      Backtrace
      • 13. app/Models/Banner.php:95
      • 14. app/Http/helpers.php:404
      • 17. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 18. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    • select count(*) as aggregate from `uc_cart_products` where cart_id='605b81a5c11e101aaa42411ac938d31d'
      310μsalphaeurekaselec_live_10_06_2022Cart.php#271
      Backtrace
      • 15. app/Models/Cart.php:271
      • 16. view::layouts._header:260
      • 18. vendor/laravel/framework/src/Illuminate/Filesystem/Filesystem.php:124
      • 19. vendor/laravel/framework/src/Illuminate/View/Engines/PhpEngine.php:58
      • 20. vendor/laravel/framework/src/Illuminate/View/Engines/CompilerEngine.php:73
    App\Models\Keywords
    15Keywords.php#?
    App\Models\Chapter
    1Chapter.php#?
    App\Models\Ebook
    1Ebook.php#?
        _token
        Ptjzx1HEGbtWG8NzZ2nJ1g5rs4czCL5XXQBzZ3bw
        uc_cart_id
        605b81a5c11e101aaa42411ac938d31d
        _previous
        array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/5540" ]
        _flash
        array:2 [ "old" => [] "new" => [] ]
        PHPDEBUGBAR_STACK_DATA
        []
        path_info
        /chapter/5540
        status_code
        200
        
        status_text
        OK
        format
        html
        content_type
        text/html; charset=UTF-8
        request_query
        []
        
        request_request
        []
        
        request_headers
        0 of 0
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        request_cookies
        0 of 0
        array:1 [ "wayfindertarget" => null ]
        response_headers
        0 of 0
        array:5 [ "content-type" => array:1 [ 0 => "text/html; charset=UTF-8" ] "cache-control" => array:1 [ 0 => "no-cache, private" ] "date" => array:1 [ 0 => "Tue, 25 Feb 2025 20:33:33 GMT" ] "set-cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlQ2N0xOTy9DZFh0R2k1TG5QeDhFcHc9PSIsInZhbHVlIjoiNHRDOGJrNmFsdHI0WENsK2FzZTQ0UzJud2hoRVptM2xiMUZkUG9JZWJaMjRQUG9EcENWVGdsYWVvVU5raXozdkx5M1RSdVM3Vi8rVkk0YWpxc1ZMbWllc0NLam5OTjBEWDdkOWNXTXFBUFl3a0RXZ0toZE1UVFptK2pQNTh5Z2QiLCJtYWMiOiJlODNhZTlhODNjZWM0Zjk1NjFmNjhjMWNmYjM5MWY4ZDI5YzY3MGMxZDQ5NjBkZTA3ZjhhYmFhNGQ3MmFhYjU2IiwidGFnIjoiIn0%3D; expires=Fri, 28 Feb 2025 08:33:33 GMT; Max-Age=216000; path=/; secure; samesite=laxXSRF-TOKEN=eyJpdiI6IlQ2N0xOTy9DZFh0R2k1TG5QeDhFcHc9PSIsInZhbHVlIjoiNHRDOGJrNmFsdHI0WENsK2FzZTQ0UzJud2hoRVptM2xiMUZkUG9JZWJaMjRQUG9EcENWVGdsYWVvVU5raXozdkx5M1RSd" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjIzOVhHMStWaU9oLzRaTGo3dGk3Tnc9PSIsInZhbHVlIjoiM3BBUVg3MHBxa2JaK29wSVVoNTc0TlhUWTBWNEp4TXBOT3pZWEo4WlBkM3FZc0dUVFptc0lRQW43NkxoS3lDeDBCckFZTkpla0cxVlViSExVRzZ6OGhjUHpJUXhzS1VCK2xMWDB0QmNXQ09qSUswNU5TZXEyYXdrUjA2aFo3bjgiLCJtYWMiOiJiOTkyNjljMTJjODVlNzdmOGMxZjJmYWVhOTg1MjRmYTZmOGMzNWE1YmE1NzY2NTFjMDIwNDM0NjFlZWM2MTg5IiwidGFnIjoiIn0%3D; path=/; secure; httponly; samesite=laxalphaeurekaselectnet_session=eyJpdiI6IjIzOVhHMStWaU9oLzRaTGo3dGk3Tnc9PSIsInZhbHVlIjoiM3BBUVg3MHBxa2JaK29wSVVoNTc0TlhUWTBWNEp4TXBOT3pZWEo4WlBkM3FZc0dUVFptc0lRQW4" ] "Set-Cookie" => array:2 [ 0 => "XSRF-TOKEN=eyJpdiI6IlQ2N0xOTy9DZFh0R2k1TG5QeDhFcHc9PSIsInZhbHVlIjoiNHRDOGJrNmFsdHI0WENsK2FzZTQ0UzJud2hoRVptM2xiMUZkUG9JZWJaMjRQUG9EcENWVGdsYWVvVU5raXozdkx5M1RSdVM3Vi8rVkk0YWpxc1ZMbWllc0NLam5OTjBEWDdkOWNXTXFBUFl3a0RXZ0toZE1UVFptK2pQNTh5Z2QiLCJtYWMiOiJlODNhZTlhODNjZWM0Zjk1NjFmNjhjMWNmYjM5MWY4ZDI5YzY3MGMxZDQ5NjBkZTA3ZjhhYmFhNGQ3MmFhYjU2IiwidGFnIjoiIn0%3D; expires=Fri, 28-Feb-2025 08:33:33 GMT; path=/; secureXSRF-TOKEN=eyJpdiI6IlQ2N0xOTy9DZFh0R2k1TG5QeDhFcHc9PSIsInZhbHVlIjoiNHRDOGJrNmFsdHI0WENsK2FzZTQ0UzJud2hoRVptM2xiMUZkUG9JZWJaMjRQUG9EcENWVGdsYWVvVU5raXozdkx5M1RSd" 1 => "alphaeurekaselectnet_session=eyJpdiI6IjIzOVhHMStWaU9oLzRaTGo3dGk3Tnc9PSIsInZhbHVlIjoiM3BBUVg3MHBxa2JaK29wSVVoNTc0TlhUWTBWNEp4TXBOT3pZWEo4WlBkM3FZc0dUVFptc0lRQW43NkxoS3lDeDBCckFZTkpla0cxVlViSExVRzZ6OGhjUHpJUXhzS1VCK2xMWDB0QmNXQ09qSUswNU5TZXEyYXdrUjA2aFo3bjgiLCJtYWMiOiJiOTkyNjljMTJjODVlNzdmOGMxZjJmYWVhOTg1MjRmYTZmOGMzNWE1YmE1NzY2NTFjMDIwNDM0NjFlZWM2MTg5IiwidGFnIjoiIn0%3D; path=/; secure; httponlyalphaeurekaselectnet_session=eyJpdiI6IjIzOVhHMStWaU9oLzRaTGo3dGk3Tnc9PSIsInZhbHVlIjoiM3BBUVg3MHBxa2JaK29wSVVoNTc0TlhUWTBWNEp4TXBOT3pZWEo4WlBkM3FZc0dUVFptc0lRQW4" ] ]
        session_attributes
        0 of 0
        array:5 [ "_token" => "Ptjzx1HEGbtWG8NzZ2nJ1g5rs4czCL5XXQBzZ3bw" "uc_cart_id" => "605b81a5c11e101aaa42411ac938d31d" "_previous" => array:1 [ "url" => "http://alpha.eurekaselect.com/chapter/5540" ] "_flash" => array:2 [ "old" => [] "new" => [] ] "PHPDEBUGBAR_STACK_DATA" => [] ]
        ClearShow all
        Date ↕MethodURLData
        #12025-02-25 20:33:33GET/chapter/55401121917