1. ¹INSERM U 713, Douleurs et Stress, Faculté de Médecine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris Cedex 13, France
2. ²INSERM U 288, NeuroPsychoPharmacologie Moléculaire, Cellulaire et Fonctionnelle, CHU Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75013 Paris, France

Correspondence: Michel Pohl, INSERM U 713, Faculté de Médecine Pitié-Salpêtrière, 91, Boulevard de l'Hôpital, 75634 Paris Cedex 13, France. Fax: +33 1 40 77 97 90. E-mail: pohl@ext.jussieu.fr

^*These authors contributed equally to this work.

Received 7 October 2004; Accepted 17 December 2004.

Abstract

Trigeminal neuropathic pain represents a real challenge to therapy because commonly used drugs are devoid of real beneficial effect or patients frequently become intolerant or refractory to some of these compounds. In a rat model of trigeminal neuropathic pain, which shares numerous similarities with human trigeminal neuralgia and trigeminal neuropathic pain, we used a genomic herpes simplex virus-derived vector (HSVLatEnk) to examine the possible effect of a local overproduction of proenkephalin A (PA) targeted to the trigeminal primary sensory neurons. Unilateral peripheral inoculation of recombinant vectors on the vibrissal pad territory resulted in an about ninefold increase in proenkephalin A mRNA levels in trigeminal ganglion ipsilateral to the infected side. Transgene-derived met-enkephalin accumulated in numerous nerve cell bodies of trigeminal ganglion and was transported through the sensory nerve fibers located in the infraorbital nerve. Bilateral mechanical hyperresponsiveness, which developed 2 weeks after chronic constrictive injury of the left infraorbital nerve, was significantly attenuated in animals overproducing PA in the trigeminal ganglion ipsilateral to the lesioned infraorbital nerve. This antiallodynic effect was reversed by both the opioid receptor antagonist naloxone and the peripherally acting antagonist naloxone methiodide. Our data demonstrate that the local overproduction of PA-derived peptides in trigeminal ganglion sensory neurons evoked a potent antiallodynic effect through the stimulation of mainly peripherally located opioid receptors and suggest that targeted delivery of endogenous opioids may be of interest for the treatment of some severe forms of neuropathic pain.