Analgesic properties of loperamide differ following systemic and local administration to rats after spinal nerve injury.

BACKGROUND: The analgesic properties and mechanisms of loperamide hydrochloride, a peripherally acting opioid receptor agonist, in neuropathic pain warrant further investigation. METHODS: We examined the effects of systemic or local administration of loperamide on heat and mechanical hyperalgesia in rats after an L5 spinal nerve ligation (SNL). RESULTS: (1) Systemic loperamide (0.3-10 mg/kg, subcutaneous in the back) dose dependently reversed heat hyperalgesia in SNL rats, but did not produce thermal analgesia. Systemic loperamide (3 mg/kg) did not induce thermal antinociception in naïve rats; (2) systemic loperamide-induced anti-heat hyperalgesia was blocked by pretreatment with intraperitoneal naloxone methiodide (5 mg/kg), but not by intraperitoneal naltrindole (5 mg/kg) or intrathecal naltrexone (20 µg/10 µL); (3) local administration of loperamide (150 µg), but not vehicle, into plantar or dorsal hind paw tissue induced thermal analgesia in SNL rats and thermal antinociception in naïve rats; (4) the analgesic effect of intraplantar loperamide (150 µg/15 µL) in SNL rats at 45 min, but not 10 min, post-injection was blocked by pretreatment with an intraplantar injection of naltrexone (75 µg/10 µL); (5) systemic (3.0 mg/kg) and local (150 µg) loperamide reduced the exaggerated duration of hind paw elevation to noxious pinprick stimuli in SNL rats. Intraplantar injection of loperamide also decreased the frequency of pinprick-evoked response in naïve rats. CONCLUSIONS: These findings suggest that both systemic and local administration of loperamide induce an opioid receptor-dependent inhibition of heat and mechanical hyperalgesia in nerve-injured rats, but that local paw administration of loperamide also induces thermal and mechanical antinociception.

Bipolar spinal cord stimulation attenuates mechanical hypersensitivity at an intensity that activates a small portion of A-fiber afferents in spinal nerve-injured rats.

Spinal cord stimulation (SCS) is used clinically to treat neuropathic pain states, but the precise mechanism by which it attenuates neuropathic pain remains to be established. The profile of afferent fiber activation during SCS and how it may correlate with the efficacy of SCS-induced analgesia are unclear. After subjecting rats to an L5 spinal nerve ligation (SNL), we implanted a miniature quadripolar electrode similar to that used clinically. Our goal was to determine the population and number of afferent fibers retrogradely activated by SCS in SNL rats by recording the antidromic compound action potential (AP) at the sciatic nerve after examining the ability of bipolar epidural SCS to alleviate mechanical hypersensitivity in this model. Notably, we compared the profiles of afferent fiber activation to SCS between SNL rats that exhibited good SCS-induced analgesia (responders) and those that did not (nonresponders). Additionally, we examined how different contact configurations affect the motor threshold (MoT) and compound AP threshold. Results showed that three consecutive days of SCS treatment (50 Hz, 0.2 ms, 30 min, 80-90% of MoT), but not sham stimulation, gradually alleviated mechanical hypersensitivity in SNL rats. The MoT obtained in the animal behavioral study was significantly less than the Aα/ß-threshold of the compound AP determined during electrophysiological recording, suggesting that SCS could attenuate mechanical hypersensitivity with a stimulus intensity that recruits only a small fraction of the A-fiber population in SNL rats. Although both the MoT and compound AP threshold were similar between responders and nonresponders, the size of the compound AP waveform at higher stimulation intensities was larger in the responders, indicating a more efficient activation of the dorsal column structure in responders.