Spinal cord stimulation reduces hypersensitivity through activation of opioid receptors in a frequency‐dependent manner

Abstract

Spinal cord stimulation (SCS) is used for the management of chronic intractable neuropathic pain. While used clinically, it is unclear if SCS produces its effects by activation of opioid receptors. The current study aimed to determine if endogenous opioids mediate the analgesia produced by SCS at different frequencies of stimulation in rats with neuropathic pain [spared nerve injury (SNI) model]. Mechanical withdrawal thresholds of the paw were tested before and after 6 h of SCS at different frequencies (4 Hz, 60 Hz and sham) given daily for 4 days at 90% motor threshold 2 weeks after SNI. Rats were given naloxone (3-10 mg/kg/h), naltrindole (1 mg/kg/h) or were made tolerant to morphine (375 g pellets daily), and effects of SCS were tested. A dose of 3 mg/kg/h naloxone prevented the analgesia produced by 4-Hz, but not 60-Hz, SCS; 10 mg/kg/h prevented the analgesia produced by 60-Hz SCS. Naltrindole prevented the analgesia produced by 60-Hz, but not 4-Hz, SCS. In morphine-tolerant rats, 4-Hz SCS had no effect on withdrawal thresholds, but 60-Hz SCS remained effective as seen by increased withdrawal thresholds. These results suggest that both 4- and 60-Hz SCS, in part, work through opioid receptor mechanisms, with 4-Hz SCS activating μ-opioid receptors while 60-Hz SCS activated δ-opioid receptors.