Antinociceptive effects of topical mepivacaine in a rat model of HIV-associated peripheral neuropathic pain

Abstract

Background: A consequence of HIV infection is sensory neuropathy, a debilitating condition that degrades the quality of life of HIV patients. Furthermore, life-extending antiretroviral treatment may exacerbate HIV sensory neuropathy. Analgesics that relieve other neuropathic pains show little or no efficacy in ameliorating HIV sensory neuropathy. Thus, there is a need for analgesics for people with this particular pain. While lidocaine is used in the management of painful peripheral neuropathies, another local anesthetic mepivacaine, with a potentially improved bioavailability, could be utilized for the management of HIV neuropathic pain.

Methods: The efficacy of topical anesthetics was evaluated in a preclinical rodent model of painful peripheral neuropathy induced by epineural administration of the HIV envelope protein gp120 delivered using saturated oxidized cellulose implanted around the sciatic nerve. Beginning at 2 weeks following gp120 administration, the effects of local anesthetics topically applied via gauze pads were tested on heat and mechanical hyperalgesia in the hind paw. Rats were tested using several concentrations of mepivacaine or lidocaine during the following 2 weeks.

Results: By 2 weeks following epineural gp120 implantation, the ipsilateral hind paw developed significant hypersensitivity to noxious pressure and heat hyperalgesia. A short-lasting, concentration-dependent amelioration of pressure and heat hyperalgesia was observed following topical application of mepivacaine to the ipsilateral plantar hind paw. By contrast, topical lidocaine ameliorated heat hyperalgesia in a concentration-dependent manner but not pressure hyperalgesia. Equipotent concentrations of mepivacaine and lidocaine applied topically to the tail of mice significantly increased tail withdrawal latencies in the tail flick test, demonstrating that both local anesthetics attenuate responding to a brief noxious stimulus.

Conclusion: These findings showed that mepivacaine, rather than lidocaine, consistently attenuated two distinct symptoms of neuropathic pain and suggest that topical formulations of this local anesthetic could have utility in the alleviation of clinical HIV neuropathic pain.

Keywords: AIDs-related pain; acute pain; analgesia; chronic pain; distal sensory neuropathy; local anesthetics.

Figure 1

Effect of topically applied mepivacaine on mechanical hyperalgesia in rats with gp120-induced neuropathic pain. Notes: (A) Effects of several concentrations (in millimolars) of topical mepivacaine or vehicle on hind paw withdrawal thresholds (in grams). Withdrawal thresholds before application of gp120 to the sciatic nerve (“pre-gp120”) and 2 weeks after, prior to topical application (“predrug”), were measured. Rats were tested within 1 minute (“immediate”) of removal of the gauze pad, and 5 and 10 minutes following removal of the gauze pad. Data are presented as mean ± standard error of the mean (n=7–10 animals per treatment group). (B) Percent changes in mechanical withdrawal thresholds following topical mepivacaine treatment, calculated from predrug baseline scores in (A). (C) Percent of animals in each concentration group reaching ≥33% increase in mechanical withdrawal threshold from predrug baselines. *P<0.05, **P<0.01, and ***P<0.001 vs vehicle-treated rats.

Figure 2

Effect of topically applied mepivacaine on thermal hyperalgesia in rats with gp120-induced neuropathic pain. Notes: (A) Effects of several concentrations (in millimolars) of topical mepivacaine or vehicle on hind paw withdrawal latencies (in seconds). Withdrawal latencies before application of gp120 to the sciatic nerve (“pre-gp120”) and 2 weeks after, prior to topical application (“predrug”), were measured. Rats were tested within 1 minute (“immediate”) of removal of the gauze pad, and 5 and 10 minutes following removal of the gauze pad. Data are presented as mean ± standard error of the mean (n=7–10 animals per treatment group). (B) Percent changes in thermal withdrawal latencies following topical mepivacaine treatment, calculated from predrug baseline scores in (A). (C) Percent of animals in each dose group reaching ≥33% increase in thermal withdrawal latencies from predrug baselines. *P<0.05, **P<0.01, and ***P<0.001 vs vehicle-treated rats.

Figure 3

Effect of topically applied lidocaine on mechanical hyperalgesia in rats with gp120-induced neuropathic pain. Notes: (A) Effects of several concentrations (in millimolars) of topical lidocaine or vehicle on hind paw withdrawal thresholds (in grams). Withdrawal thresholds before application of gp120 to the sciatic nerve (“pre-gp120”) and 2 weeks after, prior to topical application (“predrug”), were measured. Rats were tested within 1 minute (“immediate”) of removal of the gauze pad, and 5 and 10 minutes following removal of the gauze pad. Data are presented as mean ± standard error of the mean (n=7–10 animals per treatment group). (B) Percent changes in mechanical withdrawal thresholds following topical lidocaine treatment, calculated from predrug baseline scores in (A). (C) Percent of animals in each dose group reaching ≥33% increase in mechanical withdrawal threshold from predrug baselines. *P<0.05, vs vehicle-treated rats.

Figure 4

Effect of topically applied lidocaine on thermal hyperalgesia in rats with gp120-induced neuropathic pain. Notes: (A) Effects of several concentrations (in miilimolars) of topical lidocaine or vehicle on hind paw withdrawal latencies (in seconds). Withdrawal latencies before application of gp120 to the sciatic nerve (“pre-gp120”) and 2 weeks after, prior to topical application (“predrug”), were measured. Rats were tested within 1 minute (“immediate”) of removal of the gauze pad, and 5 and 10 minutes following removal of the gauze pad. Data are presented as mean ± standard error of the mean (n=7–10 animals per treatment group). (B) Percent changes in thermal withdrawal latencies following topical lidocaine treatment, calculated from predrug baseline scores in (A). (C) Percent of animals in each dose group reaching ≥33% increase in thermal withdrawal latencies from predrug baselines. Asterisks indicate differences between lidocaine treatment compared with saline-treated rats: *P<0.05.

Figure 5

Effects of topically applied mepivacaine and lidocaine on acute nociception in the mouse tail flick assay. Notes: (A) Effects of several concentrations (in millimolars) of topical mepivacaine, lidocaine, or vehicle on tail flick withdrawal latencies (in seconds). Withdrawal latencies were measured before application of drug to the tail (“baseline”). Mice were tested within 1 minute (“immediate”) of removal of the tail from the topical solution, and 5 and 10 minutes following removal of the tail from the topical solution. Data are presented as mean ± standard error of the mean (n=7–10 animals per treatment group). (B) Percent changes in tail flick latencies following topical anesthetic treatment, calculated from predrug baseline scores in (A). (C) Percent of animals in each dose group reaching ≥33% increase in tail flick latencies from predrug baselines. *P<0.05, **P<0.01 vs vehicle-treated mice.