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

Abstract

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 pinprickevoked 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.

Stronger Antinociceptive Efficacy of Opioids at the Injured Nerve Trunk Than at Its Peripheral Terminals in Neuropathic Pain

“…After spinal nerve ligation, m-receptors were downregulated in the DRG (Kohno et al, 2005;Lee et al, 2011); i.pl. m-receptor agonists attenuated hypersensitivity in few studies (Pertovaara and Wei, 2001;Guan et al, 2008;Chung et al, 2012), with one exception (Cunha et al, 2010), at the time of unaltered m-receptor levels in the paw skin (Lee et al, 2011). Following CCI, m-receptor expression was either elevated (Truong et al, 2003) or unchanged (Kolesnikov et al, 2007) in the DRG, while m-receptor agonists applied to paws attenuated the hypersensitivity (Martinez et al, 2002;Obara et al, 2004Obara et al, , 2007Obara et al, , 2009; Kolesnikov et al, 2007;Hervera et al, 2011Hervera et al, , 2012 present study) or reduced Ad and C fiber excitability to mechanical stimulation after application on the skin (Schmidt et al, 2012).…”

“…Nevertheless, in the majority of studies, opioids were applied to peripheral tissues remote from the nerve lesion site, (i.e., to paws innervated by damaged nerves). Although in some studies the effects appear substantial (Obara et al, 2004(Obara et al, , 2009Kolesnikov et al, 2007;Guan et al, 2008;Chung et al, 2012;Hervera et al, 2012), other studies showed partial attenuation (Keita et al, 1995;Walker et al, 1999;Pertovaara and Wei, 2001;Martinez et al, 2002;Kabli and Cahill, 2007;Obara et al, 2007;Hervera et al, 2010Hervera et al, , 2011Gaveriaux-Ruff et al, 2011) or no improvement (Aley and Levine, 2002;Rashid et al, 2004;Cunha et al, 2010;Uchida et al, 2010) of mechanical or heat hypersensitivity. Behaviors indicative of spontaneous/ ongoing pain have not been examined so far.…”

Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

“…We ligated spinal nerve L5 of adult male Sprague-Dawley rats (200 to 350 g, Harlan Bioproducts for Science, Indianapolis, IN) using a modification of the procedure described previously [6,14]. The animals were anesthetized with isoflurane (2%, Abbott Laboratories, North Chicago, IL) delivered through a nose cone.…”

“…Peripheral opioid receptors are being increasingly studied for their analgesic potential in the treatment of chronic pain conditions [40,44]. Our recent studies have suggested that systemic and local administration of peripherally acting opioid receptor agonists, such as loperamide hydrochloride (HCl), attenuates both mechanical and heat hypersensitivity in nerve-injured rats [6,14]. Therefore, targeting the peripheral opioid system may represent a promising new therapeutic approach for alleviating neuropathic pain [36,44].…”

“…Loperamide is a MOR-preferring agonist that does not cross the blood–brain barrier after systemic administration [4,8]. Recently, we showed that systemic and local administration of loperamide can attenuate neuropathic mechanical and heat hypersensitivity [6,14,48]. Although peripherally acting opioids have potential clinical benefits owing to the minimal risk of central dose-limiting adverse effects (sedation, cognitive dysfunction) and lack of addiction and abuse potential, it remains to be determined whether repeated systemic and local administration of peripherally restricted opioids induces tolerance to their pain-inhibitory effects under neuropathic pain conditions.…”