Antinociceptive and anti-allodynic effects of oral PL37, a complete inhibitor of enkephalin-catabolizing enzymes, in a rat model of peripheral neuropathic pain induced by vincristine.

Vincristine is a common anti-cancer therapy administered for the treatment of many types of tumors. Its dose-limiting side effect is the production of peripheral neuropathy, resulting in chronic neuropathic pain in many patients. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in male rats and used in the present work to study the effects of PL37, an orally active complete dual inhibitor of enkephalin-catabolizing enzymes, on mechanical hypersensitivity and allodynia and on cold allodynia. We used the Electronic Von Frey filament (mechanical static allodynia), acetone test (cold allodynia), and a new behavioural test we first describe in this study, the "paint-brush test" which evaluates dynamic mechanical allodynia and dynamic mechanical hypersensitivity. We used a smooth paint brush leading to an innocuous stimulus, and a rough-one leading to an intense mechanical stimulus. Mechanical hypersensitivity and allodynia due to vincristine-induced neuropathy, but not cold allodynia, are strongly reduced by oral or i.p. injected PL37, the dose-dependent effects being reversed by naloxone-methiodide supporting the peripheral action of the dual inhibitor. These results show that enkephalins protected from degradation by PL37 could bind to peripheral opioid receptors expressed only on C- and Adelta-mechanonociceptors but not on cold thermonociceptors. The fact that PL37 is also active on small intensity mechanical stimulus could reveal an expression of opioid receptors on low threshold mechanoreceptors in the vincrisitine-evoked pathological conditions. Thus the increase in endogenous enkephalin levels induced by PL37 offers a new way to reduced neuropathic pain without the possible side effects of opiates.