Abstract
Chronic pain is a major healthcare problem that impacts one in five adults across the globe. Current treatment is compromised by dose-limiting side effects including drowsiness, apathy, fatigue, loss of ability to function socially and professionally as well as a high abuse liability. Most of these side effects result from broad suppression of excitatory neurotransmission. Chronic pain states are associated with specific changes in the efficacy of synaptic transmission in the pain pathways leading to amplification of non-noxious stimuli and spontaneous pain. Consequently, a reversal of these specific changes may pave the way for the development of efficacious pain treatment with fewer side effects. We have recently described a high-affinity, bivalent peptide TAT-P4-(C5)2, enabling efficient targeting of the neuronal scaffold protein, PICK1, a key protein in mediating chronic pain sensitization. In the present study, we demonstrate that in an inflammatory pain model, the peptide does not only relieve mechanical allodynia by targeting PICK1 involved in central sensitization, but also by peripheral actions in the inflamed paw. Further, we assess the effects of the peptide on novelty-induced locomotor activity, abuse liability, and memory performance without identifying significant side effects.
Highlights
Worldwide, 1.5 billion people are suffering from chronic pain (Goldberg and McGee, 2011)
We have shown that TAT-P4-(C5)2 provides full relief of mechanical allodynia in the spared nerve injury (SNI) model of neuropathic pain following i.t. administration, but not following i.pl. administration (Christensen et al, 2020)
On day 2, the paw withdrawal threshold (PWT) of the animals was measured and consistent with previous studies (Atianjoh et al, 2010; Aoki et al, 2014), i.pl. injection of Complete Freund’s Adjuvant (CFA) led to mechanical allodynia of the ipsilateral paw, with no effect on the contralateral paw; i.e., the gram forces needed to induce paw withdrawal of the ipsilateral hind paw, was significantly lower after CFA injection compared to baseline (Figure 1B; Saline; p < 0.0001, TAT-P4-(C5)2; p < 0.0001 ; Figure 1C; Saline; p < 0.0001, 20 μM TAT-P4-(C5)2; p < 0.0001, 200 μM TAT-P4-(C5)2; p < 0.0001, morphine; p < 0.0001, two-way ANOVA followed by Dunnett post hoc test of baseline vs. day 2), which is a behavioral indication of mechanical allodynia
Summary
1.5 billion people are suffering from chronic pain (Goldberg and McGee, 2011). The treatment strategies available leave the majority of these people in more or less constant pain (Goldberg and McGee, 2011; Mills et al, 2019), in part due to the low efficacy of pain relief with numbers needed to treat (NNT) ranging from 6 to 10 (Finnerup et al, 2015; Reinecke et al, 2015; Mills et al, 2019). Chronic pain conditions are characterized by neuropathic as well as inflammatory aspects (Xu and Yaksh, 2011) and while the initial damage is often peripheral (with notable exceptions being traumatic central insults), chronic pain involves central plasticity both in the spinal cord and supraspinal areas (Hartmann et al, 2004; Nagy et al, 2004; Gangadharan et al, 2011; Tan and Kuner, 2021)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
