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.

Capsaicin responses in heat-sensitive and heat-insensitive A-fiber nociceptors.

The recently cloned vanilloid receptor (VR1) is postulated to account for heat and capsaicin sensitivity in unmyelinated afferents. We sought to determine whether heat and capsaicin sensitivity also coexist in myelinated nociceptive afferents. Action potential (AP) activity was recorded from single A-fiber nociceptors that innervated the hairy skin in monkey. Before intradermal injection of capsaicin (10 microg/10 microl) into the receptive field, nociceptors were classified as heat-sensitive (threshold,

Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers.

Ligation and transection of the L5 spinal nerve in the rat lead to behavioral signs of pain and hyperalgesia. Discharge of injured nociceptors has been presumed to play a role in generating the pain. However, A fibers, but not C fibers, in the injured L5 spinal nerve have been shown to develop spontaneous activity. Moreover, an L5 dorsal root rhizotomy does not reverse this pain behavior, suggesting that signals from other uninjured spinal nerves are involved. We asked if abnormal activity develops in an adjacent, uninjured root. Single nerve fiber recordings were made from the L4 spinal nerve after ligation and transection of the L5 spinal nerve. Within 1 d of the lesion, spontaneous activity developed in approximately half of the C fiber afferents. This spontaneous activity was at a low level (median rate, seven action potentials/5 min), originated distal to the dorsal root ganglion, and was present in nociceptive fibers with cutaneous receptive fields. The incidence and level of spontaneous activity were similar 1 week after injury. The early onset of spontaneous activity in uninjured nociceptive afferents could be the signal that produces the central sensitization responsible for the development of mechanical hyperalgesia. Because L4 afferents comingle with degenerating L5 axons in the peripheral nerve, we hypothesize that products associated with Wallerian degeneration lead to an alteration in the properties of the adjacent, uninjured afferents.

Uninjured C-fiber nociceptors develop spontaneous activity and alpha-adrenergic sensitivity following L6 spinal nerve ligation in monkey.

We investigated whether uninjured cutaneous C-fiber nociceptors in primates develop abnormal responses after partial denervation of the skin. Partial denervation was induced by tightly ligating spinal nerve L6 that innervates the dorsum of the foot. Using an in vitro skin-nerve preparation, we recorded from uninjured single afferent nerve fibers in the superficial peroneal nerve. Recordings were made from 32 C-fiber nociceptors 2-3 wk after ligation and from 29 C-fiber nociceptors in control animals. Phenylephrine, a selective alpha1-adrenergic agonist, and UK14304 (UK), a selective alpha2-adrenergic agonist, were applied to the receptive field for 5 min in increasing concentrations from 0.1 to 100 microM. Nociceptors from in vitro control experiments were not significantly different from nociceptors recorded by us previously in in vivo experiments. In comparison to in vitro control animals, the afferents found in lesioned animals had 1) a significantly higher incidence of spontaneous activity, 2) a significantly higher incidence of response to phenylephrine, and 3) a higher incidence of response to UK. In lesioned animals, the peak response to phenylephrine was significantly greater than to UK, and the mechanical threshold of phenylephrine-sensitive afferents was significantly lower than for phenylephrine-insensitive afferents. Staining with protein gene product 9.5 revealed an approximately 55% reduction in the number of unmyelinated terminals in the epidermis of the lesioned limb compared with the contralateral limb. Thus uninjured cutaneous C-fiber nociceptors that innervate skin partially denervated by ligation of a spinal nerve acquire two abnormal properties: spontaneous activity and alpha-adrenergic sensitivity. These abnormalities in nociceptor function may contribute to neuropathic pain.