Role of opioid receptors in the reduction of formalin-induced secondary allodynia and hyperalgesia in rats

This study assesses the effects of peripheral or intrathecal pre-treatment or post-treatment with µ, δ, κ and nociceptin/orphanin FQ (NOP) opioid receptor agonists (morphine, U-50488 [trans-(±)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetamide hydrochloride], DADLE [D-Ala2-Leu5-enkephalin] and nociceptin, respectively) on formalin-induced secondary mechanical allodynia and hyperalgesia in rats. 1% Formalin injection produced acute nociceptive behaviors (flinching and licking/lifting) followed by long-term tactile secondary allodynia and hyperalgesia. Neither peripheral (into the formalin-injected paw) nor intrathecal morphine post-treatment reversed formalin-induced secondary allodynia and hyperalgesia. In contrast, morphine pre-treatment prevented the development of these pain behaviors. Intrathecal and peripheral post- but not pre-treatment with U-50488 or DADLE significantly reduced secondary allodynia and hyperalgesia. Interestingly, nociceptin reduced both pain behaviors regardless of the administration site or treatment time. Local antinociceptive effects of morphine, DADLE, U-50488 or nociceptin were blocked by naltrexone, naltrindole, 5-guanidinonaltrindole and [Nphe1]nociceptin(1–13)NH2, respectively. These results suggest that the long-term nociceptive behaviors induced by formalin are differentially modulated by selective opioid receptor agonists. In addition, data suggest that peripheral and spinal δ and κ opioid receptors are important when nociceptive behaviors are established. In contrast, µ opioid receptors are more important at the beginning of the injury when the sensory system has not changed. NOP receptors participate diminishing both the development and maintenance of nociceptive behaviors. Results suggest that a barrage of afferent input induced by formalin injection initiates a long-term differential change in peripheral and spinal processing that affect the efficacy of opioid receptor agonists.