Pain Perception

Pubmed search for xanthine and pain reveals multiple articles demonstrating the association between xanthine (x) and two precursors, hypoxanthine (i), and xanthosine (Xo) with pain perception, e.g. PMID XXXX.

Inosine and guanine show promise as anti-nocioception agents with minimal toxicity PMID 20132210

Xanthine-similar structures are shared between OTC analgesics, morphinans, barbiturates, non-morphinan opiates, and veterinary agents with abuse potential.

anaquinazolin B potential

Morphinan-similar opiate blockers, including naltrexone and burprenorphine, retain xanthine-similarity and can be used to address chronic pain independent of blocking the opiate receptor.

Opiods affects purine metabolism 19760630

Lidocaine has a xanthine-similar structure. Tetracaine and benzocaine have a structure similar to 8-amino hypoxanthine: 8-amino guanosine is used in the lab as a specific PNP inhibitor, decreasing production of xanthine. IMG

Buspirone has a xanthine-similar structure, and has been shown to affect nocioception associated with depression PMID 31418663, functional abdominal pain in adolescent patients PMID 32221160, and seems to be mediated by calcium channels also sensitive to xanthine caffeine in mice PMID 12552360.  These similarities were exploited in the creation of novel KUMP-1, with the addition of MPTP-similar structure common in antipsychotics, expected to reduce conversion of Xo into x and Io into i, with demonstrated benefit in nociception in models PMID 24669856.

Duloxetine (review PMID 17012978) and fluphenazine (alone in model organism, PMID 17891479, in combination in humans PMID 11014390, 3911140, 10842546) have both been associated with improved pain control and clinically correlate to reduced hypoxanthine and secondarily decreased xanthine. Duloxetine's specific benefit in fibromyalgia suggests that fibromyalgia may be mediated by xanthine pain pathways.

Acetaminophen toxicity is frequent. There is evidence that pretreatment with PNP inhibitors amlodipine (xanthosine analogue), allopurinol, or lisinopril (hypoxanthine analgues), reduces toxicity due to acetaminophen PMID 27829805.  In light of apparent purine mechanisms/ structural similarities, decreasing endogenous sources of xanthine decreases xanthine-analogue (acetaminophen) toxicity. IMG

Acetaminophen toxicity is treated with N-acetyl cysteine, a xanthine analogue. IMG

Diabetic neuropathyis a common syndrome. Considering xanthine to play a major role in insulin resistance, it is possible that excess xanthine is also interpreted in the pain pathways mentioned here. Gabapentin, one of the most frequent treatments for diabetic neuropathy, has a xanthine-similar structure that might assist in blocking this signal. IMG

Several autoimmune diseases are primarily treated with purine-similar small molecules: IBD is frequently treated with 6-mercaptopurine, with new small-molecule treatments including tofacitinib and upadacitinib includine prominent purine-similar structures. Kawasaki disease is primarily treated with aspirin, one of the few indications in children due to the risk of Reye's syndrome, which also tightly correlates brain and hepatic function. Other NSAIDs and valproic acid (all xanthine analogues) may also precipitate Reye's syndrome PMID 33282307. Immune responses to purine modulation are well understood. IMG