The effects of mexiletine, desipramine and fluoxetine in rat models involving central sensitization

Abstract

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10-100 mg/kg, s.c.) significantly (P < 0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1-100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P < 0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3-30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different.

Spinal d-Amino Acid Oxidase Contributes to Neuropathic Pain in Rats

“…(Cook et al, 1987;Woolf et al, 1994). Our observed specific analgesia produced by sodium benzoate suggests that DAO is involved in central (spinal) sensitization in pain, as both pain models used (spinal nerve ligation-induced neuropathic pain and formalin-induced hyperalgesia) are generally believed to be mediated by central sensitization (Kim and Chung, 1992;Coderre et al, 1993;Jett et al, 1997). The mechanism for this is not known.…”

“…Last, both systemic and intrathecal administrations of sodium benzoate blocked formalin-induced hyperalgesia, in a inhibitory degree similar to that for spinal nerve ligation-induced neuropathic pain. It is known that both formalin-induced hyperalgesia and spinal nerve ligation-induced neuropathic pain share a common mechanism of central sensitization for pain states (Kim and Chung, 1992;Coderre et al, 1993;Jett et al, 1997). Together with the literature revealing that DAO measured by histochemical detection was localized predominantly in the gray matter of the medulla and spinal cord (Kapoor and Kapoor, 1997), our results suggest that spinal DAO significantly contributes to neuropathic pain and is a potential target molecule for the treatment of neuropathic pain.…”

“…Subcutaneous injection of formalin produces biphasic behavioral effects in rats, with the early phase reflecting an acute nociceptive state followed by the late phase reflecting a state of persistent hyperalgesia, which involves central sensitization (Coderre et al, 1993;Jett et al, 1997). Central sensitization is an increase in excitability of spinal and brain neurons after persistent nociceptive stimulation.…”

“…Tight ligation of L 5 and L 6 spinal nerves in rats produces mechanical allodynia and heat hyperalgesia mediated by central sensitization, representing characteristic neuropathic pain syndromes in humans (Kim and Chung, 1992;Jett et al, 1997). This study included the following procedures: 1) examining expression and activity changes of the spinal DAO, as well as development of neuropathic pain (mechanical allodynia) after L 5 /L 6 spinal nerve ligation; 2) testing the analgesic actions of the competitive DAO inhibitor sodium benzoate by systemic injection in neuropathic rats; and 3) further determining whether systemic administration of sodium benzoate exerts its analgesic effect through inhibition of spinal DAO activity by measuring spinal DAO activity and testing the analgesic effect of intrathecally injected sodium benzoate.…”

Altered antinociceptive efficacy of tramadol over time in rats with painful peripheral neuropathy

“…Pre-clinical studies that have evaluated analgesic treatments for neuropathic pain have tested them within a relatively early time frame, for example, between one to two weeks following nerve injury (Jett et al, 1997;Joshi et al, 2006). Clinicians have noted that early diagnosis and intervention will lead to better pain relief than in patients with late-stage neuropathic pain, thus, the positive outcomes in pre-clinical drug studies may be due to early testing periods (Bonica, 1990).…”