Increased expression of the Gaba B receptor gene during treatment with buprenorphine leads to methamphetamine tolerance in the lumbar spinal cord of rats

Abstract In response to psychostimulants, γ-aminobutyric acid type B receptor (GabaB) and G-protein-regulated inward-rectifier potassium channel 2 (Girk2) are activated, causing dopaminergic neuronal excitability. Buprenorphine (BUP), an opioid with mixed agonist-antagonist activity, has been approved for opioid dependency treatment and as an analgesic. Reports suggest that µ receptor agonists, which open potassium channels in neurons, significantly relieve pain, possibly due to a connection with the Girk₂ and GabaB receptors genes. This study examined methamphetamine (METH) addiction tolerance and changes in these gene expression levels during treatment with BUP. 16 groups of Wistar rats (n = 7) were randomly divided, including control, saline, METH (10 mg/kg), BUP (6 or 10 mg/kg), BUP (6 or 10 mg/kg) + METH, and withdrawal. A five- or fourteen-day intraperitoneal injection of BUP was given. After injections, a tail-flick test was performed. On the last day, these gene expressions were measured in the lumbar-spinal cord rats using qRT-PCR. These findings showed METH + BUP (10 mg/kg; 5 days) exhibited the greatest analgesia. Analgesia was enhanced after 5 days compared with 14 days. GabaB gene expression was also increased in the BUP + METH and BUP-alone groups. In the BUP group alone, Girk2 expression increased. It appears that tolerance develops with continued drug use, requiring higher doses to achieve the initial effect. However, higher doses are associated with a higher risk. Incremental expression of GabaB genes in BUP-related groups also denotes their association with analgesia. These genes are reduced in the METH-related groups.