Continuous intrathecal (IT) morphine infusion is used in chronic pain patients. A limitation is that morphine results in an inflammatory cell mass (granuloma) arising from the meninges. We recapitulated these observations in a canine model wherein lumbar CSF concentrations leading to granulomas were comparable to those observed in humans. In the last two funding cycles of this grant, we showed that granulomas are induced in a concentration dependent fashion by morphine and other opiates and not at all by fentanyl or alfentanil. We hypothesized that the granuloma arises from the degranulation of meningeal mast cells (MMC). Thus: i) opiates that degranulate MMCs ex vivo and cutaneous flare after subcutaneous (SQ) delivery produce a granuloma; ii) the meningeal/subcutaneous degranulation/flare and the granuloma are blocked by the MC stabilizer cromolyn, but not by opiate antagonism. The origin of this opiate receptor-independent MC degranulation is hypothesized to reflect the cationic properties of the nonpeptide and peptide opioid ligands acting to degranulate mast cells through G protein coupled receptor families, such as the Mas-related gene like receptors (MrgX). These observations jointly lead to an elaboration of hypotheses to characterize and avoid the granuloma. Hypothesis 1: Degranulation of mast cells by opioid agents is independent of opiate receptor activation but potentially depend upon receptors activated by cationic charge (MrgX; HFPR). Hypothesis 2. The opiate granuloma is independent of opiate receptor activation but will covary with ability of the nonpeptide and peptide opioid ligands to degranulate mast cells. In hypothesis 1, we will examine concentration dependent effects of opioid (DAMGO, TAPP, DALGA, and DMT- DALGA) and nonopioid peptides (ziconotide) and non-peptides (e.g. baclofen, clonidine, neostigmine) on: flare in the dog, mast cell degranulation in human primary mast cell cultures and on murine primary cell cultures. Using the human mast cell cultures, we will examine the role of MgrX-r using shRNA to reduce that protein expression and define the role of that cationic receptor on mast cell degranulation. In hypothesis 2, we will i) undertake dose response curves in dogs with IT infusion of the above mentioned mu opioid peptides to define the just maximally effective analgesic dose: JMEAD and the maximum tolerable (e.g. acute side effect limited) dose (MTD), ii) define intrathecal PK of selected agent and iii) determine if infusion of the maximum equi-effective (analgesic) doses of these peptides lead to a granuloma.

Public Health Relevance

Spinal opiate infusion is a recognized chronic pain therapy and spinal masses (granulomas) are a recognized risk of its use. Our work has implicated meningeal mast cells and the present activity will define the ability of agents with high opioid potency and a low propensity for mast cell degranulation to reduce the likelihood of spinal granuloma formation at analgesic doses. We believe these findings and proposed studies have great clinical relevance to developing safer agents for spinal therapy.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DA015353-10
Application #
9097668
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Rapaka, Rao
Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Podvin, Sonia; Yaksh, Tony; Hook, Vivian (2016) The Emerging Role of Spinal Dynorphin in Chronic Pain: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol 56:511-33
Yaksh, Tony L; Fisher, Casey; Hockman, Tyler et al. (2016) Current and Future Issues in the development of spinal agents for the management of pain. Curr Neuropharmacol :
Gendron, Louis; Cahill, Catherine M; von Zastrow, Mark et al. (2016) Molecular Pharmacology of δ-Opioid Receptors. Pharmacol Rev 68:631-700
Cai, Yunxin; Lu, Dandan; Chen, Zhen et al. (2016) [Dmt(1)]DALDA analogues modified with tyrosine analogues at position 1. Bioorg Med Chem Lett 26:3629-31
Yaksh, Tony L; Allen, Jeffery W; Veesart, Samantha L et al. (2013) Role of meningeal mast cells in intrathecal morphine-evoked granuloma formation. Anesthesiology 118:664-78
Hamurtekin, Emre; Fitzsimmons, Bethany L; Shubayev, Veronica I et al. (2013) Evaluation of spinal toxicity and long-term spinal reflex function after intrathecal levobupivaciane in the neonatal rat. Anesthesiology 119:142-55
Yaksh, Tony L; de Kater, Annelies; Dean, Robin et al. (2012) Pharmacokinetic analysis of ziconotide (SNX-111), an intrathecal N-type calcium channel blocking analgesic, delivered by bolus and infusion in the dog. Neuromodulation 15:508-19; discussion 519
Yaksh, Tony L; Steinauer, Joanne J; Veesart, Samantha L et al. (2012) Alfentanil: Correlations Between Absence of Effect Upon Subcutaneous Mast Cells and Absence of Granuloma Formation After Intrathecal Infusion in the Dog. Neuromodulation :
Walker, Suellen M; Yaksh, Tony L (2012) Neuraxial analgesia in neonates and infants: a review of clinical and preclinical strategies for the development of safety and efficacy data. Anesth Analg 115:638-62
Walker, Suellen M; Grafe, Marjorie; Yaksh, Tony L (2012) Intrathecal clonidine in the neonatal rat: dose-dependent analgesia and evaluation of spinal apoptosis and toxicity. Anesth Analg 115:450-60

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