Primary afferent input critical for maintaining spontaneous pain in peripheral neuropathy

Abstract

Central sensitization after peripheral nerve injury may result in ectopic neuronal activity in the spinal cord dorsal horn, implying a potential autonomous pain-generating mechanism. This study used peripheral nerve blockade and systemic lidocaine administration, with detailed somatosensory assessment, to determine the contribution of primary afferent input in maintaining peripheral neuropathic pain. Fourteen patients with neuropathic pain (7 with unilateral foot pain due to peripheral nerve injury and 7 with bilateral pain in the feet due to distal polyneuropathy) underwent comprehensive characterization of somatosensory function by quantitative sensory testing. Patients were then administered an ultrasound-guided peripheral nerve block with lidocaine and intravenous lidocaine infusion in randomized order. The effect of these interventions on spontaneous pain intensity and on evoked cold, warm, pinprick, and brush responses was assessed at each session. All patients had sensory disturbances at baseline. The peripheral nerve block resulted in a complete abolition of ipsilateral pain within 10 min (median) in all patients, with lidocaine plasma concentrations being too low to account for a systemic effect of the drug. Intravenous lidocaine infusion reduced the spontaneous pain by 45.5% (±31.7%), and it reduced mechanical and thermal hypersensitivity in most patients who displayed such signs. However, the improvement in evoked hypersensitivity was not related to the effect of the drug on spontaneous pain intensity. This study demonstrated that regardless of the individual somatosensory phenotype and signs of central sensitization, primary afferent input is critical for maintaining neuropathic pain in peripheral nerve injury and distal polyneuropathy.

Ameliorative potential of angiotensin-converting enzyme inhibitor (ramipril) on chronic constriction injury of sciatic nerve induced neuropathic pain in mice

“…22 Bradykinin is an endogenous nonapeptide which is catabolised by ACE. ACE inhibitors increase the level of bradykinin by reduction of catabolic action of BK (1)(2)(3)(4)(5)(6)(7)(8)(9) . BK (1)(2)(3)(4)(5)(6)(7)(8)(9) produces the pain sensation by direct stimulation of nociceptors in the peripheral nervous system but this effect is of very short duration of action and its half-life is very short (15 seconds).…”

“…ACE inhibitors increase the level of bradykinin by reduction of catabolic action of BK (1)(2)(3)(4)(5)(6)(7)(8)(9) . BK (1)(2)(3)(4)(5)(6)(7)(8)(9) produces the pain sensation by direct stimulation of nociceptors in the peripheral nervous system but this effect is of very short duration of action and its half-life is very short (15 seconds). 23 In addition, BK (1)(2)(3)(4)(5)(6)(7)(8)(9) is not only degraded by ACE but also by other enzymatic pathways, i.e.…”

“…BK (1)(2)(3)(4)(5)(6)(7)(8)(9) produces the pain sensation by direct stimulation of nociceptors in the peripheral nervous system but this effect is of very short duration of action and its half-life is very short (15 seconds). 23 In addition, BK (1)(2)(3)(4)(5)(6)(7)(8)(9) is not only degraded by ACE but also by other enzymatic pathways, i.e. aminopeptidase P, carboxypeptidase, dipeptidyl peptidase IV, endothelin-converting enzyme, neprilysin, propyl oligopeptidase, and the neutral endopeptidase.…”

Targeting angiotensin II type 2 receptor pathways to treat neuropathic pain and inflammatory pain

“…This latter notion is supported by clinical trial data showing that EMA401 produced analgesia above placebo in patients with PHN by the third week of treatment but without CNS side effects [9]. Our view that ongoing ectopic primary afferent input is key to the maintenance of peripheral neuropathic pain is supported by observations that ultrasound-guided peripheral nerve blocks with lidocaine in patients with distal polyneuropathy and peripheral nerve injury produced ipsilateral analgesia in the absence of clinically relevant systemic lidocaine exposure [48].…”

Opioids and TRPV1 in the peripheral control of neuropathic pain – Defining a target site in the injured nerve

“…injections (Labuz and Machelska, 2013); this could result from opioid receptor up-regulation and their enhanced accessibility by agonists due to the blood-nerve barrier disruption at the nerve damage site (Abram et al, 2006;Stein and Machelska, 2011;Schmidt et al, 2013). Although such injection site-related comparisons were not performed for sodium channel blockers, perineural lidocaine completely abolished spontaneous, mechanical and thermal pain in patients with traumatic nerve injury (Haroutounian et al, 2014). In naïve animals, functional TRPV1 were found along the M A N U S C R I P T…”