The Opioid Receptor‐4 (OP4) Is Involved In The Spinal Plasticity During The Development Of Neuropathic Pain In The Rat

Abstract

Nociceptin (N/OFQ), possibly acting through its receptor (OP4), shows anti‐nociceptive properties when administered in the spinal cord of neuropathic rats (Yamamoto et al., 1998; Hao et al., 1999). OP4 has also been described as a mediator of spinal facilitation occurring in the chronic constriction injury (CCI) rat model (Yamamoto et al., 2000). Thus, we studied the spinal effect of N/OFQ in this model and the molecular changes that occurred in both lumbar enlargement and dorsal root ganglia (DRG) of neuropathic rats. The sciatic nerve of rodents was unilaterally ligated following the Bennett & Xie (1988) procedure and their mechanical pain threshold was recorded by von Frey hairs. Rats responding to non‐noxious stimuli (<3.6 g) displayed allodynic‐like behaviour and were selected for pharmacological studies. N/OFQ (0.2–20 nmol) injected intrathecally (i.t.) in rats induced a dose‐dependent anti‐allodynic activity. Five min post drug administration, a rise in the pain threshold was observed with 2 nmol [(23.9 g (18.3–31.5) vs 2.9 g (1.9–4.4) of the control group; p < 0.01]. This effect was OP4‐mediated as the receptor antagonist, [Nphe1]N/OFQ(1–13)NH2 (60–120 nmol; Guerrini et al., 2000), prevented the activity of N/OFQ [9.8 g (4.3–22.1) and 6.17 g (2.2–17.3) vs 34.7 g (14.5–82.7) in the N/OFQ treated group, 5 min post injection; p < 0.05 and p < 0.01, respectively]. The two described OP4 splice variants (Xie et al., 1999) were up‐regulated in the ipsilateral spinal tissues of allodynic rats. The short form increased by 100% while the long form increased by 50%vs control values in the spinal cord. In the DRG, both isoforms of OP4 were increased by 60 and 50%, respectively. This up‐regulation is time‐dependent and it is closely related to the allodynic‐like behaviour. On the contrary, the mRNA expression of either the OP4 receptor or the preproN/OFQ was not modified in either side of the lumbar spinal cord or DRG. Moreover, OP4 knockout mice showed a marked decrease in thermal pain threshold after CCI as measured by the plantar test. These results demonstrate a modulation of OP4 expression in the development of mechano‐allodynia in the CCI rat model. Further studies are necessary to clarify the function of OP4 receptor reorganization in the spinal plasticity occurring in persistent pain.