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Mechanism of intrathecal Contulakin-G induced analgesia without motor block

Award Number: K08NS104272
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 11/15/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2025

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Mechanism of intrathecal Contulakin-G induced analgesia without motor block - Effective treatment of high-impact pain patients is one the major stated goals of the National Pain Strategy. Although implanted intrathecal drug delivery system that takes advantage of spinal pain processing mechanisms is highly effective in most intractable pain patients, their use is limited primarily because of the side effects such as tolerance, psychosis and motor block associated with drugs used in them (opioids, ziconotide, local anesthetics). Novel analgesics that take advantage of spinal pain processing, are safe to use in humans and have minimal motor block and tolerance can be revolutionary in the management of high-impact pain. Contulakin-G (CGX) is a snail venom derived peptide that has homology with mammalian neurotensin has been shown to be safe in humans and a small, pilot Phase1A study demonstrated its analgesic effect. Prior published studies and our preliminary data demonstrate that intrathecal CGX is analgesic in various intractable pain conditions with minimal tolerance and motor block. However, the mechanism behind the analgesia without motor block and the receptor signaling pathway elicited by CGX is not known. Our preliminary data suggest that CGX activates neurotensin receptor 2 (NT2) to inhibit the R-type voltage gated calcium channels (VGCC). Interestingly, although NT2 is present in both sensory and motor neurons, R-type VGCC expression is more selective in pain neurons and possibly some motor neurons. In this project, we propose to test an innovative hypothesis that spinal CGX produces analgesia without motor block is secondary to CGX activation of neurotensin receptor 2 (NT2) leading to inhibition of R-type VGCC in sensory but not motor neurons. We propose to study the central hypothesis both in vitro (SA1) and in vivo (SA2). We incorporate cutting edge scientific tools such as CRISPR-Cas9 editing and proximity ligation assay coupled with highly validated in vitro and in vivo assays to address these questions. The proposed studies test a novel hypothesis with high translational significance and they also serve as a career development mechanism for a highly trained, interventional pain physician and pharmacologist who is mentored by accomplished pain scientists with a strong pedigree of successful mentees. Data from these studies will not only form the basis of a subsequent R01 application and allow the applicant to be an independently funded clinician scientist but have the potential to lead to clinical advancement of a nonopioid drug in a patient population that desperately needs relief.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/19/2024	NON-COMPETING CONTINUATION	-$8,151
2024	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/19/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$8,151
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	9/8/2023	NON-COMPETING CONTINUATION	-$141,354
2023	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	9/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$141,354
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $197,640 )
2022	2022	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/13/2022	NON-COMPETING CONTINUATION	$197,640
														Subtotal = $197,640

Issue Date FY: 2021 ( Subtotal = $197,640 )
2021	2021	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/20/2021	NON-COMPETING CONTINUATION	$197,640
														Subtotal = $197,640

Issue Date FY: 2020 ( Subtotal = $197,640 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/28/2020	NON-COMPETING CONTINUATION	$197,640
														Subtotal = $197,640

Issue Date FY: 2019 ( Subtotal = $197,640 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/8/2019	NON-COMPETING CONTINUATION	$197,640
														Subtotal = $197,640

Issue Date FY: 2018 ( Subtotal = $196,560 )
2018	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/12/2018	NEW	$196,560
														Subtotal = $196,560

Grand Total All Awards = $987,120

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Mechanism of intrathecal Contulakin-G induced analgesia without motor block

Award Number: K08NS104272

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 11/15/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2025

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