α7 nicotinic acetylcholine receptor potentiation modulates cytokine/chemokines and brain derived neurotrophic factor in the central nervous system of mice: implications in decreased neuropathic pain and associated comorbidities.

OBJECTIVES: This study evaluates whether PAM-4, a positive allosteric modulator of the α7 nicotinic acetylcholine receptor, can reverse neuropathic pain and associated affective disturbances caused by oxaliplatin (OXA) in male mice and whether they are linked to alterations in cytokine/chemokine and brain-derived neurotrophic factor (BDNF) levels in different central nervous system (CNS) areas. METHODS: Mice were first treated with OXA to induce neuropathic pain and associated anxiety- and depressive-like symptoms in mice, and the activity of PAM-4 subsequently determined. Cytokine/chemokine and BDNF levels were also assessed in various CNS areas dissected from treated animals. KEY FINDINGS: The behavioral results indicated that PAM-4 significantly alleviated neuropathic pain and comorbidities induced by OXA. Concurrently, PAM-4 diminished OXA-induced increase in chemokine/cytokine levels across multiple tissues, especially in the spinal cord and hippocampus. Furthermore, PAM-4 restored the levels of pro BDNF and mature BDNF in the spinal cord and brain. Most effects mediated by PAM-4 were attenuated by the selective antagonist methyllycaconitine (MLA), whereas MLA alone also reduced the effects of OXA in few cases, suggesting that although α7 nAChR potentiation is the primary mechanism, receptor inhibition may also play a role. CONCLUSION: α7 nAChR modulation effectively alleviates neuropathic pain and associated comorbidities induced by chemotherapy, along with a decrease in neuroinflammatory markers and rebalancing of BDNF signaling.