Opioid receptors mRNAs expression and opioids agonist-dependent G-protein activation in the rat brain following neuropathy

Potent opioid-based therapies are often unsuccessful in promoting satisfactory analgesia in neuropathic pain. Moreover, the side effects associated with opioid therapy are still manifested in neuropathy-like diseases, including tolerance, abuse, addiction and hyperalgesia, although the mechanisms underlying these effects remain unclear. Studies in the spinal cord and periphery indicate that neuropathy alters the expression of mu-[MOP], delta-[DOP] or kappa-[KOP] opioid receptors, interfering with their activity. However, there is no consensus as to the supraspinal opioidergic modulation provoked by neuropathy, the structures where the sensory and affective-related pain components are processed. In this study we explored the effect of chronic constriction of the sciatic nerve (CCI) over 7 and 30 days (CCI-7d and CCI-30d, respectively) on MOP, DOP and KOP mRNAs expression, using in situ hybridization, and the efficacy of G-protein stimulation by DAMGO, DPDPE and U-69593 (MOP, DOP and KOP specific agonists, respectively), using [35S]GTPγS binding, within opioid-sensitive brain structures. After CCI-7d, CCI-30d or both, opioid receptor mRNAs expression was altered throughout the brain: MOP – in the paracentral/centrolateral thalamic nuclei, ventral posteromedial thalamic nuclei, superior olivary complex, parabrachial nucleus [PB] and posterodorsal tegmental nucleus; DOP – in the somatosensory cortex [SSC], ventral tegmental area, caudate putamen [CPu], nucleus accumbens [NAcc], raphe magnus [RMg] and PB; and KOP – in the locus coeruleus. Agonist-stimulated [35S]GTPγS binding was altered following CCI: MOP - CPu and RMg; DOP - prefrontal cortex [PFC], SSC, RMg and NAcc; and KOP - PFC and SSC. Thus, this study shows that several opioidergic circuits in the brain are recruited and modified following neuropathy.This study was supported by grants co-financed by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Ciencia, Innovación y Universidades (RTI2018-099778-B-I00) and the “Instituto de Salud Carlos III (PI18/01691)); the “Consejería de Salud de la Junta de Andalucía” (PI-0134-2018); the “Programa Operativo de Andalucía FEDER, Iniciativa Territorial Integrada ITI 2014-2020 Consejería Salud, Junta de Andalucía” (PI-0080-2017); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510); the “Centro de Investigación Biomédica en Red de Salud Mental-CIBERSAM” (CB/07/09/0033; CB/07/09/0029)